Charge Transfer-Oxy Radical Mechanism for Anti-Cancer Agents
Marquette University e-Publications@Marquette
Chemistry Faculty Research and Publications Chemistry, Department of
11-1-1986 Charge Transfer-oxy Radical Mechanism for Anti- cancer Agents Peter Kovacic University of Wisconsin - Milwaukee
James R. Ames University of Wisconsin - Milwaukee
Paavo Lumme University of Helsinki
Hannu Elo University of Helsinki
O. Cox University of Puerto Rico, Rio Piedras
See next page for additional authors
Published version. Anti-Cancer Drug Design, Vol. 1, No. 3 (November 1986): 197-214. Publisher link. © 1986 Cognizant Communication Corporation. Used with permission. Authors Peter Kovacic, James R. Ames, Paavo Lumme, Hannu Elo, O. Cox, and Michael D. Ryan
This article is available at e-Publications@Marquette: https://epublications.marquette.edu/chem_fac/600 Anti-Cancer Drug Design (1986), 1, 197-214
Charge transfer-oxy radical mechanism for ,anti-cancer agents1
1 1 2 2 3 3 P. Kovacic , J.R. Ames , P. Lumme , H. Elo , 0. Cox , H. Jackson , L.A. 3 3 4 : Rivera , L. Ramirez & M.D. Ryan 1Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201 USA, 2Department of Inorganic Chemistry, University of Helsinki, Vuorik 20, SF -00100, Helsinki, Finland, 3Department of Chemistry, Universi-ty of Puerto Ricq, Rio Piedras, Puerto Rico 00931, and 4 Department of Chemistry, Marquette University, Milwaukee, WI 53233, USA
Summary: The proposal is advanced that anti -cancer drugs generally function by charge transfer resulting in formation of toxic oxy radicals which destroy the neoplasm. Electrochem ical studies were performed with some of the main types of agents: iminium ions (adenine iminium from alkylating species, iminium metabolite of 6-mercaptopurine, nitidine, other polynuclear iminiums) and metal complexes (Pt(II)diaquodiammine-guanosine, copper salicylaldoximes). Reduction potentials ranged from -0.4 to -1.2 V. Literature data for quinones are presented and radiation is discussed. Based on the theoretical framework, a rationale is offered for the carcinogen-anti-cancer paradox and the role of antioxidants.
More than two decades ago the oxy radical oxide, and inert bodies (Kovacic et al., in for carcinogenesis was advanced press). & Guzman Barron, 1951; Holman, The initial inklings (Holman, 1956; War 1956; Harman, 1956). Shortly thereafter, the burg et al., 1957) that reactive oxy species proposal was placed on a broader, more may play a role in anti-cancer action was systematic foundation (Harman, 1962; Kov shortly followed by a better developed, . acic, 1959 and 1960). This approach received more comprehensive approach (Kovacic, scant attention until fairly recent times 1959). A baffling paradox of oncology is the which have witnessed ever increasing well-known phenomenon that generally the support from a variety of disciplines (Ames, substances which induce cancer are also 1983; Mason, 1982; Demopoulos et al., 1980). antineoplastic. If the premise is valid th.at In general terms, the comprehensive theory these agents cause cancer by producing states that oxy radicals are implicated in the excessive amounts of oxy radicals, it may action of most carcinogens, arising as the well be that their ability to combat the end product of metabolic processes, usually condition is intimately related to the same . via charge transfer (CT). Apparently, the chemical property. An essential component highly reactive radicals subsequently attack of the overall picture is the corollary that cellular DNA, as well as other crucial many tumor cells are more susceptible than constituents, resulting in transformation to normal ones to elevated concentrations of '. the oncogenic state. Specific application has oxy radicals, thus providing the requisite · been made to alkylating agents, quinones, specificity. Supporting evidence may be metal complexes, iminium ions .. radiation, found from the early days of oncology carbon tetrachloride, 4-nitroquinoline 1- (Kovacic, 1959), as well as newer data which will be presented in the discussion section. 1 Presented in part at the 189th national meeting, American Chemical Society, Miami, FL, MEDI Abstr Recently the suggestion was made that acts, 81 (1985). iminium species (1), usually in conjugated Correspondence: P. Kovacic. form, play important roles biologically in a
© The Macmillan Press Ltd, 1986 j<;J ~;;~J -. ;~r~ 198 P. KOVACIC et al. ;;{~ ·!'% . _;-~:;:7 variety of redox transformations (Kovacic, 0 1984). These entities might then function· :~~:~~::~~, !~g~7e~i~g ~h~ lo;ci ~~;cJp~~ :::(Ql catalytically at the active site as electron tate (Marcelis et al., 1980). The solution was
+
2
3 4 SOH so 2z t~) N}0--N N . I l NJl N\) H I H 5 a)Z=H b)Z=Na CH30
6 a)R 1+R 2 =CH2 b)R1=H R2=CH 3 7
8 a)R=H b)R=OCH3
9
Cu+2tOXfR) ~ I N=C 2 I I HO H
a) R=H b) R=OH
,, 12 generally function as carcinogens (Miller In a recent investigation of the & Miller, 1983). Concomitant production mechanism of carcinogenesis, a novel of oxy radicals has been observed with proposal was advanced in which the salt various members (Ames, 1983; Floyd, form (iminium) of alkylated nucleic acid 1982). Although the precise role of these was assigned a key function as aCT agent reactive intermediates has not been (Kovacic et al., in press). The purines ascertained, it appears that DNA strand (guanine and adenine) of DNA are the cleavage may be a crucial event (Floyd, principal targets of attack (Miller and 1982). Miller, 1983). For example, the ionic 200 P. KOVACIC et al.
structure 2, a conjugated form of iminium (1) is generated from 0-6 alkylation of guanine and could conceivably undergo !1 mA one-electron reduction. Electrochemical data from the literature (Dryhurst, 1977) and our own studies (Kovacic et al., in press) are in reasonable accord with the current picture relating site of alkylation and defect persistence to oncogenic response. Thus, it appears quite plausible that the salt form is functioning in a 0.0 -0.5 -1.0 catalytic manner as a generator of toxic oxy v radicals. In order to test this concept as applied Figure 1 Cyclic voltammogram of 4 in DMF, Pt to anti-cancer alkylating agents, salts electrode, scan rate 100mVIs. derived from alkylation of adenine and adenosine were investigated electro chemically as models. 3-Benzyladenine positive figure obtained for the reduction chloride 3 gives irreversible reduction potential was -0.96 V (DMF) (Figure 1, values of about -1.0 V (Table I). Upon Table 1). The results were less favorable in addition of strong base the potentials DMSO. The product of the reduction is become more negative and the current probably a dimer, since coupling has been drops until, with excess base, there is no observed from electrolysis of purine bases reduction before the background current, in non-aqueous solvent (Yao et al., 1976). due to generation of the nonreducible, Our data are in agreement with nonionic base via loss of HCl. Occurrence previous investigations with adenine in of this transformation was confirmed by aqueous acid. E112 values, -1.05 to electrochemical studies on the free base -1.07 V, were reported, which varied which gave no reduction before back . linearly with pH (Dryhurst, 1977). ground. A second model consisted of the Adenosine and adenylic acid behaved nucleoside with the base alkylated at a similarly. Evidently salt formation oc- · different site, namely, N-1. For 1- curs by preferential protonation at N-1 · methyladenosine iodide 4, the most (Saenger, 1984). There are several possible sites adenine alkylation. The preferred one in. Table I Cyclic voltammetry of N-alkylated vivo is generally the N-1 position. adeninium and adenosinium halides.a Reaction at N-7 is also common! observed, whereas N-3 attack varies -Ep degree (Shooter, 1972; Rajalakshmi al., 1982). Alkylation at any of the [OH-] mM Compound DMF DMSO positions would produce a potential 3-Benzyl adenine 0.96 1.00 agent capable of catalytic operation. chloride 0.49 1.03 1.19 N-3 position has been suggested as 0.99 b - b important locale in the carcino b b 3-Benzyladenine - - process (Lijinsky, 1976). It is .,J·,F. ... ,, ...... u ••• (',., 1-Methyladenosine 0.96 1.23 that N-7 adenine salts possess ph iodide 0.49 0.96 1.23 logical activity (Iio et al., 1985). b b 0.99 - - (b) 6-Mercaptopurine: The properties _ this drug are summarized in Table Vll. a 100 mV/s, tetraethylammonium perchlorate (0.1 M), substrate (0.5 mM), Pt electrode, irreversible, vs. SCE. It, as well as related materials, · b No reduction of substrate before background evidently converted to the corresp reduction. ing nucleotide (Ishiguro et al., 1984) CHARGE TRANSFER-OXY RADICAL MECHANISM 201 the nucleoside (Chabner, 1981; Christie Table III Electrochemistry of fused derivatives of et al., 1984) followed by insertion into quinolinium and isoquinolinium salts.a the DNA chain. The thiol appears to be oxidized to the unstable sulfenic acid 5 -EP which undergoes further conversion to Electrode Compound DMF DMSO H20b techniquec the isolable sulfinic acid 6a (Hyslop & Jardine, 1981; Nelson, 1982). The acids 7a 0.90 d - d Hg,P could exist in an ionic (iminium) form 1.07 1.09 - d Pt,CV (cf. 2) either from intra- or intermolecu - d - d 1.15 Hg,CV lar nuclear protonation. 7b 0.99 - d - d Hg,P Since an oxidative metabolite is 1.01 - d 0.89 Hg,CV thought to be the active agent, we 1.11 1.14 - d Pt,CV 8 1.24 d - d Hg,P obtained data on the reduction potential d for 6. In DMF the EP varies from -1.0 V 1.25 - 1.35 Hg,CV 1.34 1.35 - d Pt,CV for the iminium from nuclear protona d 9a 0.39, 1.18 0.42, 1.12 - Hg,P tion to > -2.0 V for the sodium salt (6b) 0.42, 1.19 0.45, 1.17 - d Hg,CV (Table II). In aqueous buffer 6 exhibits 0.65, 1.21 0.64, 1.16 - d Pt,CV potentials (V) that vary linearly with pH 9b 0.42, 1.18 0.45, 1.12 - d Hg,P (Ep = -0.44-0.100 pH); the most posi 0.45, 1.20 0.47, 1.16 - d Hg,CV tive value was -0.77 V (pH 3.3). Hence 0.66, 1.17 0.67, 1.17 - d Pt,CV reduction is facilitated by increasing acidity. The results in aqueous media a 100mvIS, tetraethylammonium perchlorate (TEAP, are in agreement with data (V) from an 0.1 M), substrate (0.5 mM), vs. SCE. b Buffer (KHP) pH 6, no TEAP. earlier study (Dryhurst, 1969) in which 6 c P-polarography, CV--cyclic voltammetry. exhibited E112 = -0.37-0.094 pH (pH 1- d Not examined electrochemically. 9.1). Reduction involved the N-1=C-6 bond giving the dihydro product (Dry 5 should reduce at a value between hurst, 1977). Also included were the those for 6b and the disulfide. parent thiol, E112 = -0.79-0.116 pH (pH 0-5), purine 6-sulfonic acid, E112 = -0.45-0.078 pH (pH 1-7), and 6- 2. Fused derivatives of quinolinium and iso purinyldisulfide, E112 = -0.0 V. From quinolinium salts.. This class is represented these findings Dryhurst concluded that by the alkaloids nitidine 7a and fagaronine
Table II Cyclic voltammetry of purine-6-sulfinic acid.a
[Acid] mM DMF H20b
>2.0 - c c HC104 0.46 1.24 - HC10 0.91 1.03, 1.23 - c 4 c HC104 1.3 1.00, 1.22 - HOAc pH3.3 0.77 HOAc pH3.9 - c 0.83 HOAc pH4.8 - c 0.92
a 100 mV/s, tetraethylammonium per -0 6 -1 0 -1.4 chlorate (0.1 M, DMF), 6b (0.5 mM), HMDE v vs. SCE, irreversible. b HOAc/OAc- buffer. Figure 2 Cyclic voltammogram of 7a in DMF, Pt c Not examined electrochemically. electrode, scan rate 100 mV/s. 202 P. KOVACIC et al.
7b, the indenoisoquinolinium salt 8 and 3- the 1-phenylpyridinium ion, i.e., ~E 112 was nitrobenzothiazolo(3, 2-a)quinolinium salts more negative by about 0.03 V (Zuman, 9a, b. Studies on 7 and the analogue 8 gave 1967a). values ranging from -0.90 to -1.15 V (Table The activity of 7 has been correlated with III) for 7 and -1.25 to -1.35 V for 8. The the presence of the imini urn site (Caolo & methoxyl .substituent is known to result in Stermitz, 1979), in keeping with our more negative potentials (Zuman, 1967a). theoretical framework. Also N-methylphen Cyclic voltammetry (CV) (Figure 2) gives anthridinium salts are known to undergo irreversible reductions. On the other hand, charge transfer (Parkanyi & Leu, 1975). It is calculations from polarography (P) and CV reasonable to associate the activity of 9 in indicate reversible behavior. The EP - EP12 part with nitro or the nitroso reduction (CV) and E314 - E114(P) values of 60 mV are in product, since compounds of this type are reasonable agreement with the theoretical used in cancer therapy (Docampo & values of 57(CV) and 56(P) mV for a Moreno, 1984; Murray & Meyn, 1985). These one-electron process. Isoquinolinium salts substances (7-9) may exert their activity by are known to undergo one electron reduc binding to DNA (Baez et al., 1983; Cushman tion with formation of the 1,1'-dimer et al., 1984). Related anti-tumor alkaloids (Bradsher, 1981). The nitrobenzothiazolo include coralyne (Cox et al., 1982) and quinolinium salts (9a, b) give multiple sanguinarine (Nandi & Maiti, 1985). reduction values (Table III) (Figure 3); the most positive range from -0.39 to· _:_0.65 V (irreversible). The more negative waves, 3. Ellipticines. Most members of this class about -1.2 V, are reversible. Calculations on are anti-tumor agents. Metabolites and the first wave provide values similar to various derivatives incorporate quinone those from 7, namely, 63(CV) and 60(P) mV. imine and iminium, e.g., 10. The results Apparently the reductions are followed by a from extensive studies (Paoletti et al., 1983) fast follow-up step. There are two predomi are summarized in Table VII. Electrochemi nant electroactive sites associated with 9, cal data demonstrate the ability of the namely, the nitro group and the iminium hydroxylated metabolite to function as a ion. The literature E112 for nitrobenzene is charge transfer entity (Paoletti et al., 1983). -0.62 V (Wheeler, 1963). Enhancement in Recent reviews deal with iminium ions the positive direction in our case is due to a in the alkaloid category (Knabe, 1979) and more extended, electrophilic system of from oxidative metabolism of xenobiotics conjugation. Substitution of methoxyl for (Overton et al., 1985). The iminium charge hydrogen in the benzothiazole ring has the transfer theory appears broadly applicable effect of making the reductions more to a wide variety of biologically active negative by about 0.03 V as a result of agents (Kovacic, 1984), carcinogens (Kovacic electron donation, in agreement with the et al., in press), drugs (quinoxaline-di-N reported effect of the 4-methoxyl group in oxides) (Ryan et al., 1985), MPTP (Ames et al., in press a), phencyclidine, nicotine and spermine metabolites (Ames et al., in press b), antimalarials (Ames et al., 1985c), mesoionic betaines (Ames et al., 1986d) and benzodiazepines (Crawford et al., in press).
Metal complexes Metal species are known to elicit a variety of 0.0 -0.5 -1 0 -1.5 physiological responses. Specific chemical v reactions that have been observed include Figure 3 Cyclic voltammogram of 9a in DMF, Pt oxygen radical formation (Ames, 1983;· electrode, scan rate 100mVIs. Stern, 1985) and DNA strand cleavage (Furst CHARGE TRANSFER-OXY RADICAL MECHANISM 203
& Radding, 1984) (Table VII). Formation of the same EP values ( -0.96 to -1.0 V) as for complexes with DNA is reported for some the Pt(II) precursor. The similar results may cases (Furst & Radding, 1984; Saenger, 1984) be due to involvement of supporting (Table VII). electrolyte since added salt is known to alter
the 1:1 Pt(II)(H20h(NH3h-guanoside com 1. cis-DDP. The most prominent member plex in solution (Marcelis et al., 1980). No of the anti-cancer group is cis-DDP. Several reduction occurs before background for reviews summarize much of the work trans-DDP, and the corresponding diaquo (Roberts & Thomson, 1979; Rosenberg, 1980; derivative is reduced at -1.20 V. The trans & Lippard, 1980). Binding of Pt(II) to diaquodiammine Pt(Il)-guanosine complex F.--·-~···~·- of DNA is known to occur, and is (1: 1 and 1:2 in solution) gave EP values to have marked biochemical and that are more negative ( -1.3 to -1.6 V). :~¥~:~:\ 'pharmacological significance (Pinto & Lip Thus, the reduction potentials in the cis ;z~i·'~:,._pard, 1985; ·Macquet & Theophanides, 1975; series are more positive than for the trans ·;,;(~J~~, Ciccarelli et al., 1985). Considerable effort counterparts. Since trans-DDP is less active ~&~l;}{ has been devoted to structural analysis of (Cleare, 1974) than the cis-isomer a correla t:[(: the DNA-Pt(II) complex (Sherman et al., tion exists between potency and ease of · :· 1985; Marcelis et al., 1980; Rosenberg, 1980). electroreduction, in accord with the general ~;~~;:;:: Since there is apparent conversion to the mechanistic theme. Prior rationale for the ~~z,~,· diaquodiammine metabolite in vivo (Carsey difference in activity has been summarized ,~~~i:.~ & Boudreaux, 1980), attention was centered Qohnson et al., 1985). *iK:~.·:. on this form in the electroreduction studies. The proposed pathway entailing catalytic :;,:'r:· Guanosine was used as the model ligand. production of oxy radicals is consistent with j~? Cyclic voltammetry data for the Pt com effectiveness of the Pt drug at low doses ·k• .plexes are presented in Table IV. All (Rosen~erg, 1980; Barton & Lippard, 1980). · reductions are irreversible. No reduction The toxicity is reduced by mercapto occurs before background for cis-DDP and containing compounds that are well known Experiments with the cis antioxidants (Nagy et al., 1986; Kempf et al., Pt(II)-guanosine complex 1986). Other radical scavengers such as or in solution) revealed approximately a-tocopherol and N,N' -diphenyl-p-phenyl enediamine exerted a similar effect (Sugihara Table IV Cyclic voltammetry of Pt(II) & Gemba, 1986). The investigators proposed guanosine complexes.a free radical damage by the drug. Also thiols Compound protected against mutagenesis (Nagy et al., 1986) a condition generally attributed to oxy cis-DDP NRb.c radicals (Kovacic, 1984). There is evidence trans-DDP NRb.c for a close relationship between mutagene Guanosine NRb.c sis and carcinogenesis (Slaga, 1983). Chrom cis-Pt(II)(H20 )2(NH3)2 0.96 osomal aberrations, primarily chromatid cis-Pt(II)(H20 )2(NH3h- breaks, are known to be induced by guanosine 0.96 cis-DDP (Flessel et al., 1980). cis-Pt(II)(H20 )2(NH3h guanosine (1: 1 solution) 1.0 2. Complexes of copper and iron trans-Pt(II)(H20 )2(NH3) 2 1.20 trans-Pt(II)(H20 )2(NH3)2- (a) Copper: Some copper complexes in this guanosine category 11 incorporate salicylaldoximes (1: 1 solution) 1.45 as chelating agents (Lumme et al., 1984). (1: 2 solution) 1.30, 1.60 Reduction potentials for 11a and 11b ranged from -0.86 to -0.96 V for the aPt flag, tetraethylammonium perchlorate most positive values with Pt as the (0.1 M), substrate (0.5 mM), vs. Ag/AgCl, 100 mV/ s. working el~ctrode, and from -0.71 to b No reduction. -0.86 V with Hg. All of the reductions c 200mV/s. were irreversible (Table V) (Figure 4). 204 P. KOVACIC et al.
Table V Cyclic voltarnrnetry of copper(II) related bis(thiosemicarbazone) com salicylaldoxirne complexes. a plexes display E112 values of -0.34 to -0.53 V, adjusted to SCE that are attributed to the reduction of Cu(II) to Cu(I) (Winkelmann et al., 1974). Compound DMF DMSO Electrode According to our guiding theme, there lla 0.86, 1.29 0.93, 1.34 Pt is CT resulting in toxic oxy radicals via 0.75, 1.23 0.71, 1.18 Hg superoxide. Experimental support is llb 0.91, 1.26 0.97, 1.38 Pt provided by the observation that 0.86b 0.84b, 1.28 Hg Cu(l)bis(thiosemicarbazone) is autoxi dizable by oxygen (Petering, 1972), a a 100 mV /s, tetraethylammonium perchlorate (0.1 M), process expected to produce superoxide. substrate (0.5 mM), irreversible, vs. SCE. b Reduction with adsorption. It is relevant that interaction of heterocyclic carboxaldehyde thiosemi The difference in reduction potential for carbazones with DNA was observed to lla and llb ( -0.04 to -0.05 V, Pt result in single strand cleavage (Tsifts electrode) is in agreement with the oglou et al., 1975); preliminary associa reported effect of the hydroxyl group in tion of the drug with metal may well anthrone, i.e., ~E 112 was more negative occur. DNA scission is commonly by 0.01 to 0.05 V (Zuman, 1967b). There associated with oxy radical formation has been a prior suggestion that (Demopoulos et al., 1980). Agrawal & electron transfer may play a mechanistic Sartorelli (1978) proposed that the action role in vivo (Lumme & Elo, 1985). For on DNA is of major significance for the related Cu(II)(3,5-diisopropyl cytotoxicity. salicylateh, evidence was provided to (b) Iron: Iron complexes of thiosemicarba support the contention that hydrogen zones show antineoplastic activity (Sco peroxide is partly involved in the vill et al., 1982). Compound 12 exhibits anti-tumor action (Oberley et al., 1983). a reduction wave at -0.23 V (reversible) Another class of copper(II) coordina (Ames et al., 1985c). tion compounds, the thiosemicar Proposals have been made that bazones, is known to possess anti several well-known agents function cancer activity (Petering, 1980; Scovill et after initial coordination with metal ion. al., 1982). Reduction of the complex The action of bleomycin is summarized derived from 2-acetylpyridine thiosemi in Table VII (Halliwell & Gutteridge, carbazone occurs reversibly at about 1985a). According to current thinking -0.5 V (Ames et al., 1985c). The (Hecht, 1979; Lown, 1982), the drug sequesters Fe(III) in the cell nucleus and intercalates or binds to DNA. Redox reactions involving the iron and oxygen take place. The reduction potential for the Fe(III) complex is -0.11 V adjusted to SCE (Melnyk et al., 1981). Adriamycin is known to be a chelat ing agent for a number of metal ions including Fe(II), Fe(III) and Cu(II) (Halliwell & Gutteridge, 1985a). The iron complexes bind to DNA (Gianni et al., 1985) and reduce molecular oxygen· -0.4 -1.0 -1.3 to reactive radicals. DNA cleavage is v observed. Figure 4 Cyclic voltarnrnograrn of lla, in DMF, Pt electrode, scan rate 100 rn VIs. 3. Others. Various other metals, e.g. Rh, CHARGE TRANSFER-OXY RADICAL MECHANISM 205
;-'Ru, Sn, Ti, V and Mo, in derivative form (Youngman et al., 1984). Strand scission can >;exhibit anti-cancer activity (Cleare, 1974; occur in the absence of binding. '> Cleare & Hydes, 1980; Sadler, 1982). Iminoquinones have not been as exten 1 ,. ;'However, compared to cis-DDP, they have sively studied. Representative members are -received relatively little attention. In addi 5-iminodaunorubicin (Lown et al., 1982), tion, several agents, such as, a,a' -dipyridyl anthrapyrazoles (Fry et al., 1985), and . ·(Hellman et al., 1983) and picolinic acid actinomycin D (Halliwell & Gutteridge, , .(Leuthauser et al., 1982), which are effective 1985a; Doroshow, 1983). Relevant character ;: against neoplasms, may fit into this istics are intercalation, oxy radical forma ··mechanistic category based on their ability tion, DNA cleavage, and oxygen depen ~,~ to bind metals strongly. dency. As in the quinone case, charge transfer has not been observed after intercalation (Emanuel et al., 1984; Sengupta .. Quinones and iminoquinones et al., 1985). Evidence shows that redox .: Quinone antibiotics have found widespread cycling and radical generation are less facile application in recent years in the treatment with the imine analogues (Lown et al., of malignancy (Mason,' 1982; Lown, 1982; 1979). Several other anti-cancer agents, e.g., . 1983; Waring, 1981). Results from extensive rhodamine 123 (Lampidis et al., 1983), and ::. 1 studies, which principally involved anthra an oxidative metabolite of ellipticine •"' ::".cyclines, mitomycins, streptonigrin, and (Paoletti et al., 1983), possess similar _;••2L:;.saframycins, are summarized in Table VII. structures . . >The toxicity, found to be oxygen dependent Table VI contains the reduction potentials ::<'. (Halliwell & Gutteridge, 1985a), apparently for a number of substances in this general
.,. _results from redox cycling of the quinone. category. The E112 values fall in the range, Initial metabolic reduction to the semi -0.20 to -1.09 V. A study revealed that the quinone intermediate, which can bind to anti-tumor activity of 75% of the in DNA (Sinha & Chignell, 1979) evidently is vestigated iminobenzoquinones could be an essential step (Lown, 1982; Emanuel et correctly classified based only on their al., 1984). The overall· process has been reduction potentials (Hodnett et al., 1978). designated 'site-specific free-radical' gen Also, the iminoquinones, which exhibit eration (Bachur et al., 1982). Inhibition of more negative reduction potentials than the . the rate of DNA scission was observed with quinones, were found to induce less DNA ·added catalase, superoxide dismutase and strand cleavage (Lown et (ll., 1982). The end free radical scavengers (Lown, 1982). product of anthrapyrazole reduction is the However, adriamycin bound to DNA is corresponding dihydro form (Showalter et unable to participate in redox reactions al., 1986).
Table VI Reduction potentials for some physiologically active quinones and iminoquinones.
Reduction Compound potential (V) Reference
Daunorubicin -0.62 Rao et al., 1978 Adriamycin -0.62 Rao et al., 1978 Mitomycin B -0.20 Rao et al., 1977a Mitomycin C -0.37 Rao et al., 1977b 5-Imino- daunorubicin -0.70 Lown ·et al., 1982 Anthrapyrazoles -0.98 to -1.09 Showalter et al., 1986 Actinomycin D -0.82 Nakazawa et al., 1985 206 P. KOVACIC et al.
Table VII Characteristics of anti-cancer agents.a
Generation of reactive DNA DNA Agent oxygen species bindingb cleavage Quinones + ·+ + Metals + + + Bleomycin + + + Ionizing radiation + + 6-Mercaptopurine +c + Alkylating agents + + + Ellipticined + + +
a See the discussion for references. b Intercalation or covalent. c Nucleotide insertion. d And derivatives.
The exact state in which these compounds 1-methyl-4-phenylpyridinium ion (cyper generate oxy radicals at the active site is not quat, MPTP metabolite) E112 = -1.09 V) established with certainty. Alternatively, the (Ames et al., in press, a) which display ultimate agent may be a metal complex (vide rather negative values are reported to supra). function by oxy radical generation via CT (Ryan et al., 1985; (MPTP) Markey et al., Radiation 1985). Reversibility is more likely in vivo due to immobilization of the CT agent at the Relevant biological effects are summarized active site. in Table VII (Harman, 1962; Henriksen et al., 1976; Greenstock & Whitehouse, 1984). It Other considerations is conceivable that indirect generation of oxy radicals also occurs. The nucleic acid 1. Role of oxygen. In our prior discussion, bases are considerably more sensitive than much evidence has been cited for the the phosphate backbone to radiation (Green formation and involvement of activated stock & Whitehouse, 1984). Purines are oxygen species. It is generally believed that known to form N -oxy species readily on superoxide serves as a precursor. Support exposure to peroxide (Robins, 1967), which for this standpoint is provided by in might then serve as CT precursors for vestigations on the beneficial influence of radicals (Kovacic et al., in press). For oxygen on drug and radiation effectiveness example, adenine 1-oxide displays an E112 of against cancer cells (Cadenas, 1985; Teicher -0.81 V, pH 1 (Dryhurst, 1977). Also, some et al., 1981; Gupta & Krishan, 1982). The forms of ionizing radiation apparently give conclusion was drawn that a common rise to cationic species that alkylate cellular mechanistic pathway pertains for the constituents (Seifter, et al., 1984). diverse agents (Gupta & Krishan, 1982; Correlation of reduction potential with Scheulen · & Kappus, 1984) in accord with physiological activity is not new. Examples the present thesis. Drug activity observed include anti-cancer agents (Murray & Meyn, during hypoxia (Teicher et al., 1981) can be 1985) and other categories (Hodnett et al., rationalized by reductive stress involving 1978; Bogatskii et al., 1971). radical processes Gones, 1985). There are indications from prior reports Free radicals derived from oxygen are that reduction potential in vivo may well be increasingly implicated in the initiation and more favorable than in vitro (Kaye & progression of various diseases, and in the Stonehill, 1952; Neta et al., 1985), Both di toxic action of numerous drugs and chemi oxidine (E 112 = -1.06 V) (Ryan et al., 1985) and cals (Nelson, 1982; Holtzman, 1982; Sies, CHARGE TRANSFER-OXY RADICAL MECHANISM 207
1985; Halliwell & Gutteridge, 1985). The obvious relationship between resistance to following statement also reflects a unified ionizing radiation or radical-producing approach: 'Several of the chemotherapeutic drugs and tumor cell content of the agents are thought to have both their following enzymes: Cu-Zn SOD, Mn SOD, therapeutic and toxic effects by causing an catalase, and glutathione peroxidase (Mark oxidative stress' (Holtzman, 1982). The lund et al., 1982). These findings of large natural phagocytic response to foreign variations in the effectiveness of protective bodies entails attack by activated oxygen systems may partly account for the observed entities (Baehner et al., 1982). differences in response by cancer patients. Another feature of importance is the rate 2. Crucial differences between malignant and of production of superoxide by tumors. If normal cells. As pointed out in the intro the generation is similar to or greater than duction, an important feature of the the case of normal cells, then the lowered carcinogen-anti-cancer theory is the cancer levels of protective enzymes in the neo cell property of enhanced susceptibility to plasms would result in enhanced sensitivity reactive oxygen-containing entities. This to the additional oxidative stress. Investiga postulate, advanced quite some time ago, tors have shown that tumor cell mitochon was based primarily on decreased levels of dria do produce superoxide (Oberley & catalase. Since then, other enzymes which Buettner, 1979). In one case, the rate of destroy these oxy species have been formation was nearly the same as for normal discovered and investigated (Willson, 1983). tissue, whereas in another report there was · The superoxide dismutase (SOD) enzyme a five-fold increase. . decomposes superoxide which is generated Although chemotherapy and ionizing by aerobic metabolic reactions. Presumably, radiation have proved beneficial in the protection is thereby provided from the treatment of cancer, relapse and limited adverse effects of oxy radicals, such as applicability are commonly seen (Rosen hydroxyl, which can arise from the radical berg, 1980). There are a number of possible anion. In fact, various reports reveal rationalizations (Kovacic, 1959). In the inhibition of radiation carcinogenesis by context of the theoretical interpretation, SOD (Hall & Borek, 1983). A considerable increased concentrations of oxy radicals may number of studies have found decreased not be completely effective due to the levels of SOD in malignant neoplastic survival of a small fraction of resistant tissues (Oberley & Buettner, 1979). Mn SOD cancer cells which then proliferate. This is lower in all cases vs. normal cells. The reminiscent of the scenario which has been Cu-Zn SOD levels were diminished in encountered repeatedly with drugs, in many, but not all, tumors. Glutathione secticides, and herbicides. Furthermore, a .peroxidase has also been the object of fine balance would pertain since the radicals . attention. The basic premise (Kovacic, 1959) which are generated to combat malignancy advanced more than 26 years ago has been are also capable of inducing the same confirmed (Alexander, 1983) and restated condition. Several recent studies are in after the discovery of the protective role of harmony with the dual role concept. For SOD: 'If equal amounts of superoxide can instance, the incidence of second cancers in be delivered to both cancer cells and normal an individual was increased after treatment then the cancer cell should be of the primary ones with anti-cancer drugs killed because it has lower (Huang et al., 1983). The induction of new Indeed, there is evidence neoplasms was observed as a delayed effect that many of existing cancer treatments (Harris, 1979). By the same token, initiation ., .•. , ····"·'x .•.•..·.actually are using this rationale because of cancer should entail a certain degree of many of the anti-cancer drugs have been simultaneous inhibition. In fact, early shown to produce superoxide' (Oberley & investigators have reported precisely this Buettner, 1979). However, other in type of refractory condition on application vestigators have failed to observe any • of carcinogens (Kovacic, 1959). 208 P. KOVACIC et al.
3. Alternate mechanisms. Although the oxy areas (Kinnamon et al., 1980). Perhaps some radical theory possesses many attractive of these responses are also due to oxy features, clearly it presents an over radical formation via CT. simplified picture of a complex phenome non. A number of investigations reveal the 5. Role of antioxidants. In prior sections, important involvement of other factors, the approach entailed treatment of an principally immunological reactions, inhibi established tumor. Alternatively, the prob tion of DNA synthesis, antimetabolite lem can be attacked via prevention of action, and DNA defect repair (Rosenberg, initiation by decreasing the concentration of 1980; Roberts & Thomson, 1979; Halliwell & oxy intermediates. Anti-cancer agents in Gutteridge, 1985a; Lumme et al., 1984; this category, which act as inhibitors of Paoletti et al., 1983; Cushman et al., 1984; carcinogenesis, would generally be labeled Baez et al., 1983; Doerr et al., 1961; Remy et as antioxidants (Demopoulos et al., 1980; al., 1984; Ciccarelli et al., 1985). Specific Ts'o et al., 1977). A good deal of the work examples of compounds that are generally has involved phenolic types, such as believed to operate by other routes are butylated hydroxyanisole, selenium com methotrexate (antifolate) (Cole, 1970), a pounds, vitamin E, vitamin C, and difluoromethylomithine (DFMO, ornithine ethoxyquin. These substances are expected decarboxylase inhibitor) (Metcalf et al., to be ineffective against existing neoplasms, 1978) and 5-fluorouracil (antipyrimidine) and would act only to inhibit the formation (Cole, 1970). It is noteworthy that evidence of additional ones from normal cells. suggests the possibility of CT in some cases. Here again, it is essential to bear in mind For instance, conjugated iminium species the element of specificity. To be effective the derived from pyridoxal phosphate have antioxidant must reach the site at which the been designated as intermediates in the harmful radicals are being generated. reaction of DFMO with the enzyme (Metcalf Various characteristics of the protective et al., 1978). From X-ray data on the binary agent would come to bear, including complex, N-1 protonation of the- pteridine hydrophobic and hydrophilic properies. portion of methotrexate to iminium is Hence, it is not surprising that many invoked (Bolin et al., 1982). From a study of studies reveal beneficial effects of anti the ternary. complex, the drug and NADPH oxidants, whereas others (Willet et al., 1984) were shown to be in close proximity do not. (Matthews et al. 1978). NADPH might be In conclusion, the theoretical scheme oxidized by various routes including radical entails several features common to most or CT mechanisms (Filman et al., 1982). A anti-cancer agents: metal complex may also participate (Kova cic, 1984) in the case of the pyridoxal imine 1. Binding to DNA by alkylation, complexa from DFMO. It is conceivable that several tion (minor groove), intercalation, or mechanisms operate in concert for certain incorporation within the chain as a agents. A recent unifying approach for special purine. antineoplastic agents entailed modification 2. Presence of a charge transfer entity in the of DNA (Hemminki and Ludlum, 1984). form of an iminium salt, metal complex, quinone, ArN02 or ArNO. 4. Other biological activity. In addition to 3. Formation of toxic oxy radicals via the anti-tumor property, the various agents superoxide generated by electron can display other physiological activities; transfer. carcinogenic, mutagenic, cytotoxic, and 4. Attack of vital cellular constituents by teratogenic (Magee, 1982; Johnson et al., oxy radicals resulting in death of the 1980; Miller & Miller, 1983; Furst & cancer. Radding, 1984; Fry, 1983). There is a relationship between antineoplastic activity The carcinogen-anti -cancer paradox is ra and the ability to function as drugs in other tionalized on the basis of similar mechanisms CHARGE TRANSFER-OXY RADICAL MECHANISM 209
operating in both cases; many tumor cells AMES, J.R., POTTS, K.T., RYAN, M.D. & are more susceptible than normal ones to KOVACIC, P. (1986). Conjugated and cross the toxic effects of oxy radicals. Antioxidants conjugated mesomeric betaines. Correlation of appear to function by destroying harmful electroreduction with structure and physiolog oxy species. ical activity. Life Sciences, 39, 1085. BACHUR, N.R., GEE, M.V. & FRIEDMAN, R.D. (1982). Nuclear catalyzed antibiotic free radical Acknowledgement formation. Cancer Research, 42, 1078. BAEHNER, R.L., BOXER, L.A., INGRAHAM, This work was supported by grants from the L.M. (1982). Reduced oxygen byproducts and ~Shaw Research Fund, Graduate School, Univer white blood cells. In Free Radicals in Biology. sity of Wisconsin-Milwaukee, Lynn Dennison, Vol. 5. Pryor (ed.), pp. 91-93. Academic Press: '' and GTE. We thank Professors Barbara Wells, New York. David Petering, and James Otvos for helpful BAEZ, A., 'GONZALEZ, F.A., VAZQUEZ, D. & :'; discussions, Professor Mark Cushman for the WARING, M.J. (1983). Interaction between a benzophenanthridine samples, and Dr Hollis 3-nitrobenzothiazolo(3,2-a) quinolinium anti Showalter for information prior to publication. tumor drug and deoxyribonucleic acid. Biochemical Pharmacology, 32, 2089. BARTON, J.K. & LIPPARD, S.J. (1980). Heavy metal interactions with nucleic acids. In Nucleic Acid-Metal Ion Interactions. Spiro (ed.), ABSHIRE, C.J. & BERLINGUET, L. (1964). p. 31. Wiley-Interscience: New York. Synthesis of some alkylated adenines as BOGATSKII, A.V., ANDRONATI, S.A., potential antimetabolites. Canadian Journal of GUL'TYAI, V.P. et al. (1971). 1-4-Benzodia Chemistry, 42, 1599. zepines and their derivatives. V. Polarographic AGRAWAL, K.C. & SARTORELLI, A.C. (1978). reduction and structure of 1,3- The chemistry and biological activity of dihydro-2H -1,4-benzodiazepin-2-ones and a-(N)-heterocyclic carboxaldehyde thiosemi -benzodiazepine-2-thiones. Journal of General carbazones. Progress in Medicinal Chemistry, 15, Chemistry of the USSR., 41, 1364. 349. BOLIN, J.T., FILMAN, D.J., MATTHEWS, D.A., ALEXANDER, P. {1983). Can antioxidants facili HAMLIN, R.C. & KRAUT, J. (1982). Crystal tate cancer induction? Oxidation reactions structures of Escherichia coli and Lactobacillus involved in host-mediated destruction of casei dihydrofolate reductase refined at 1.7 A cancer cells. In Radio Protectors and Anticar resolution. Journal of Biological Chemistry, 257, cinogens. Nygaard & Simic (eds), p. 575. 13650. Academic Press: New York. BRADSHER, C.K. (1981). Quaternary iso AMES, B.N. (1983). Dietary carcinogens and quinolinium salts. In Isoquinolines. Grethe anticarcinogens. Science, 221, 1256. (ed.), pp. 417-418. Wiley: New York. AMES, J.R., CASTAGNOLI, N., }R., RYAN, M.D. BRUES, A.M & GUZMAN BARRON, E.S. (1951). & KOVACIC, P. Oxidative ionic metabolites Biochemistry of cancer. Annual Reviews of of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri Biochemistry, 20, 343. dine (MPTP): Correlation of electroreduction CADENAS, E. (1985). Oxidative stress and with physiological behavior. Free Radical formation of excited species. In Oxidative Research Communications (in press, a). Stress. Sies (ed.), p. 318. Academic Press: New AMES, J.R., BRANDANGE, S., RODRIGUEZ, B., York. CASTAGNOLI, N., }R., RYAN, M.D. & CAOLO, M.A. & STERMITZ, F.R. (1979). KOVACIC, P. Cyclic voltammetry with cyclic Benzophenanthridinium salt equilibria. iminium ions. Implications for charge transfer Heterocycles, 12, 11. with biomolecules (metabolites of nicotine, CARSEY, T.P. & BOUDREAUX, E.A. (1980). The phencyclidine and spermine). Bioorganic Che electronic structure of platinum-guanine com mistry (in press, b). plexes. Chemica-Biological Interactions, 30, 189. AMES, J.R., RYAN, M.D., KLAYMAN, D.L., & CHABNER, B.A. (1981). Antineoplastic agents. KOVACIC, P. (1985). Charge transfer and oxy Nucleoside analogs. In Cancer and radicals in antimalarial action. Quinones, Chemotherapy, Antineoplastic Agents. Vol. III. dapsone metabolites, metal complexes, imin Crooke & Prestayko (eds), p. 3. Academic ium ions and peroxides. Journal of Free Radicals Press: New York. in Biology and Medicine, 1, 353. CHRISTIE, N.T., DRAKE, S., MEYN, R.E. & 210 P. KOVACIC et al.
NELSON, J.A. (1984). 6-Thioguanine-induced DOROSHOW, J.H. (1983). Effect of anthracycline DNA damage as a determinant of cytoxicity in antibiotics on oxygen radical formation in rat cultured chinese hamster ovary cells. Cancer heart. Cancer Research, 43, 460. Research, 44, 3665. DRYHURST, G. (1969). Electrochemical reduction CICCARELLI, R.B., SOLOMON, M.J., of 6-thiopurine and related compounds: VARSHAVSKY, A. & LIPPARD, S.J. (1985). In polarography, voltammetry, and macroscale vivo effects of cis- and trans-diamminedichloro electrolysis. Journal of the Electrochemical platinum(II) on SV 40 chromosomes: Society, 116, 1357 (and references therein). differential repair, DNA-protein cross-linking, DRYHURST, G. (1977). Electrochemistry of and inhibition of replication. Biochemistry, 24, purine derivatives. In Electrochemistry of 7533. Biological Molecules. Chap. 3. Academic Press: CLEARE, M.J. (1974). Transition metal complexes New York. in cancer chemotherapy. Coordination Chem EMANUEL, N.M., BOGDANOV, G.N. & istry Reviews, 12, 349. ORLOV, V.S. (1984). Free-radical mechanisms CLEARE, M.J. & HYDES, P.C. (1980). Antitumor in the cytotoxic action of antitumor antibiotics. properties of metal complexes. In Metal Ions in Russian Chemical Reviews, 53, 1121. Biological Systems. Vol. 11. Sigel (ed.), p. 1. FILMAN, D.J., BOLIN, J.T., MATTHEWS, D.A., Marcel Dekker: New York. & KRAUT, J. {1982). Crystal structures of COLE, W.H. (1970). In Chemotherapy of Cancer. Escherichia coli and Lactobacillus casei dihydro Lea & Febiger: Philadelphia. folate reductase refined at 1.7 A resolution. COX, 0., JACKSON, H., VARGAS, V.A. et al. Journal of Biological Chemistry, 257, 13663. (1982). Synthesis and biological activity of FLESSEL, C.P., FURST A. & RADDING, S.B. benzothiazolo- and benzoxazolo[3,2-a]quino (1980). A comparison of carcinogenic metals. In linium salts. Journal of Medicinal Chemistry, 25, Metal Ions in Biological Systems. Vol. 10. 1378. Carcinogenicity and Metal Ions. Sigel (ed.), COX, 0., JACKSON, H., RIVERA, L.A., Chap. 2. Marcel Dekker: New York. · RAMIREZ, L., unpublished work. FLOYD, R.A. (ed.) {1982). Free Radicals and CRAWFORD, P.W., KOVACIC, P., GILMAN, Cancer. Marcel Dekker: New York. N.W. & RYAN, M.D. Charge transfer mechan FRIDOVICH, I. (1983). Superoxide radical: an ism for benzodiazepine (BZ) action. Correla endogenous toxicant. Reviews of Pharmacology tion of reduction potential of BZ iminium with and Toxicology, 23, 239. structure and drug activity. Bioelectrochemistry FRY, D.W., BORITZKI, T.J., BESSERER, J.A. & and Bioenergetics (in press). JACKSON, R.C. (1985). In vitro DNA strand CUSHMAN, M., MOHAN, P. & SMITH, E.C.R. scission and inhibition of nucleic acid synthe (1984). Synthesis and biological activity of sis in L1210 leukemia cells by a new class of structural analogues of the anticancer ben DNA complexers, the anthra[1,9-cd] pyrazol- zophenanthridine alkaloid nitidine chloride. 6(2H)-ones (anthrapyrazoles). Biochemical Journal of Medicinal Chemistry, 27, 544. Pharmacology, 34, 3499. DEHAND, J. & JORDANOV, J. (1976). Interaction FRY, R.J.M. (1983). Radiation carcinogenesis. In of cis-diaminotolueneplatinum(II) with nucle Radioprotectors and Anticarcinogens. Nygaard & osides: evidence for guanosine 0(6).N(7) Simic (eds), p. 417. Academic Press: New York. chelation by platinum. Chemical Com FURST, A. & RADDING, S.B. (1984). New munications, 598. developments in the study of metal carcino DEMOPOULOS, H.B., PIETRONIGRO, D.D., genesis. Journal of Environmental Science and FLAMM, E.S. & SELIGMAN, M.L. (1980). The Health, C2, 103. possible role of free radical ' reactions in GIANNI, L., ZWEIER, J.L., LEVY, A. & MYERS, carcinogenesis. Journal of Environmental Path C.E. (1985). Characterization of the cycle of ology and Toxicology, 3, 273. iron-mediated electron transfer from adria DOCAMPO, R. & MORENO, S.N.J. (1984). Free mycin to molecular oxygen. Journal of Biological radical intermediates in the antiparasitic action Chemistry, 260, 6820. of drugs and phagocytic cells. In Free Radicals GREENSTOCK, C.L. & WHITEHOUSE, R.P. in Biology. Vol. 6. Pryor (ed.), p. 264. Academic (1984). Base damage in irradiated DNA and the Press: Orlando. effect of oxygen. In Oxygen Radicals in DOERR, I.L., WEMPEN, I., CLARKE, D.A. & Chemistry and Biology. Bors, Saran & Tait (eds), FOX, J.J. (1961). Thiation of nucleosides. III. p. 619. deGruyter: New York. Oxidation of 6-mercoptopurines. Journal of GUPTA, V. & KRISHAN, A. (1982). Effect of Organic Chemistry, 26, 3401. oxygen concentration on the growth and drug CHARGE TRANSFER-OXY RADICAL MECHANISM 211
sensitivity of human melanoma cells in hepatic protein in vitro. Journal of Pharmacology soft-agar clonogenic assay. Cancer Research, 42, and Experimental Therapeutics, 218, 621. 1005. 110, H., ASAO, K. & TOKOROYAMA, T. (1985). E.J. & BOREK, C. (1983). SOD protection Synthesis of agelasin B and its analogues. against oncogenic· transformation. In Radio Chemical Communications, 774. protectors and Anticarcinogens. Nygaard & ISHIGURO, K., SCHWARTZ, E.L. & _.Simic p. 515. Academic Press: New York. SARTORELLI, A.C. (1984). Characterization of B. & GUTIERIDGE, J.M.C. (1985). the metabolic forms of 6-thioguanine respon Free Radicals in Biology and Medicine. (a), Chap. sible for cytotoxicity and induction of 8. Clarendon Press: Oxford. differentiation of HL-60 acute promyelocytic D. (1956). Aging: a theory based on leukemia cells. Journal of Cellular Physiology, . free radical and radiation chemistry. Journal of 121, 383. ,~., -: .· Gerontology, 11, 298. JOHNSON, N.P., ·HOESCHELE, J.D., RAHN, ;;:~~Y}IARMAN, D. (1962). Role of free radicals in R.O., O'NEILL, J.P. & HSIE, A.W. (1980). ~~·::r>·· mutation, cancer, aging, and the maintenance Mutagenicity, cytotoxicity, and DNA binding ;:~~},;i;; of life. Radiation Research, 16, 753. of platinum(II) chloroammines in chinese t!~'tt,:HARRIS, C.C. (1979). A delayed complication of hamster ovary cells. Cancer Research, 40, 1463. ;:;>J cancer therapy-<:ancer. Journal of the National JOHNSON, N.P., MAZARD, A.M., ESCALIER, J. t;;:_,: Cancer Institute, 63, 275 . & MACQUET, J.P. (1985). Mechanism of the
. . :HECHT, S.M. (ed.) (1979). In: Bleomycin: reaction between cis-[PtC12(NH3}z] and DNA in Chemical, Biochemical, and Biological Aspects. vitro. Journal of the American Chemical Society, ::· Springer-Verlag: New York. 107, 6376. ,>('HELLMAN, R.M., GLASS, J. & NUNEZ, M.T. JONES, J.W. & ROBINS, R.K. (1963). Purine ;:;~ (1983) a,a'-Dipyridyl as an antineoplastic nucleosides. III. Methylation studies of certain naturally occurring purine nucleosides. Journal ~~~ ~~=~:~!~; s~;~~~~~ .. n~::c;~~i~~;t ~r ~~:'"l:h of the American Chemical Society, 85, 193. ~.· · International Conference. Urushizaki, Aisen & JONES, D.P. (1985). The role of oxygen :;~',•:, Listowsky (eds), p. 479. Elsevier: Amsterdam; concentration in oxidative stress: hypoxic and ;,iiy:, Chemical Abstracts (1984), 101, 48280. hyperoxic models. In Oxidative Stress. Sies ·.:\;-HEMMINKI, K. & LUDLUM, D.B. (1984). (ed.), p. 189. Academic Press: New York. i;~::·. · Covalent modification of DNA by antineo KAYE, R.C. & STONEHILL, H.l. (1952). Polar ;,~;;· : plastic agents. Journal of the National Cancer ographic reduction of some natural and ·:· .. ~"· Institute, 73, 1021. artificial hydrogen-carriers in bacterial enzyme ~,·~- .-.HENRIKSEN, T., BERGENE, R., HEIBERG, A. & systems. Journal of the Chemical Society, 3244. ~;. :· SAGSTUEN, E. (1976). Radical reactions in KEMPF, S.R., IVANKOVIC, S., WIESSLER, M. & ,.. "" nucleic acids: crystal systems. In Free Radicals SCHMAEHL, D.· (1986). Effective prevention of in Biology. Vol. 2. Pryor (ed.), p. 258. Academic the nephrotoxicity of cisplatin (CDDP) by '"·-\ Press: New York. administration of sodium 2-mercaptoethane ~_:.:: HODNETT, E.M., PRAKASH, G. & sulfonate (MESNA) in rats. British Journal of · '< AMIRMOAZZAMI, J. (1978). Nitrogen analo Cancer, 52, 937; Chemical Abstracts (1986), 104, .. . gues of 1,4-benzoquinones. Activities against 61639. :.'; the ascitic sarcoma 180 of mice. Journal of KINNAMON, K.E., STECK, E.A. & RANE, D.S.
,. 1 • Medicinal Chemistry, 21, 11. (1980). Anticancer agents and antitrypano ~,, HOLMAN, R.A. (1956). Production of abnormal somiasis activity in mice. Journal of the ~ ... · bacteria. Some possible analogies with forma- National Cancer Institute, 64, 391. , tion of tumors. Lancet, ii, 515. \; KNABE, J. (1979). Iminium salts in nature. In ··';r HOLTZMAN, J.L. (1982). Role of reactive oxygen Iminium Salts in Organic Chemistry Part 2, ';':",: and metabolite binding in drug toxicity. Life Bohme & Viehe (eds), p. 733. In Advances in , '·"·· Sciences, 30, 1. Organic Chemistry. Taylor (ed.). Wiley HUANG, C.C., HAN, C.S., YUE, X.F. et al. (1983). Interscience: New York. Cytotoxicity and sister chromatid exchanges KOVACIC, P. (1959). An integrated concept of induced in vitro by six anticancer drugs carcinogenic-anticarcinogenic action. Ohio developed in the People's Republic of China. Journal of Science, 59, 318 (and references Journal of the National Cancer Institute, 71, 841. therein). HYSLOP, R.M. & JARDINE, I. (1981). Metabolism KOVACIC, P. (1960). A proposed role for of 6-thiopurines. I. Irreversible binding of a hydrogen peroxide in carcinogenesis. Ohio metabolite of 6-thiopurine to mammalian Journal of Science, 60, 283. 212 P. KOVACIC et al.
KOVACIC, P. (1984). Does charge transfer by MACQUET, J.P. & THEOPHANIDES, T. (1975). diiminium play a widespread role in living DNA-platinum interactions in vitro with trans
systems? Kemija u Industriji, 33, 473 (and and cis-Pt(NH3)zC12 • Bioinorganic Chemistry, 5, references therein). 59. KOVACIC, P., CRAWFORD, P.W., RYAN, M.D. MAGEE, P.N. (1982). Interaction of activated & NELSON, V.C. Charge transfer mechanism intermediates of chemical carcinogens with for carcinogenesis by alkylating and other cellular DNA and its possible prevention. In agents. Bioelectrochemistry and Bioenergetics (in Free Radicals, Lipid Peroxidation, and Cancer. press). McBrien & Slater (eds), p. 353. Academic Press: LAMPIDIS, T.]., BERNAL, S.D., SUMMER New York. HAYES, I.C. & CHEN, L.B. (1983). Selective MARCELIS, A.T.M., VAN KRALINGEN, C.G. & toxiciy of rhodamine 123 in carcinoma cells in REEDIJK, J. (1980). The interactions of cis- and vitro. Cancer Research, 43, 716. trans-diammine platinum compounds with LEUTHAUSER, S.W.C., OBERLEY, L.W. & 5'-guanosine monophosphate and 5'-de OBERLEY, T.D. (1982). Antitumor activity of oxyguanosine monophosphate. A proton nmr picolinic acid in CBA/J mice. Journal of the investigation. Journal of Inorganic Biochemistry, National Cancer Institute, 68, 123. 13, 213. LIJINSKY, W. (1976). Interaction with nucleic MARKEY, S.P., CASTAGNOLI, N., DAVIS, M. et acids of carcinogenic and mutagenic N-nitroso al. (eds) (1985). Symposium on MPTP. A compounds. Progress in Nucleic Acid Research parkinsonian syndrome producing neurotoxin. and Molecular Biology, 17, 247. Uniformed Services University of the Health LOWN, J.W., CHEN, H.-H., PLAMBECK, ].A. & Sciences. Bethesda, Maryland. ACTON, E.M. (1979). Diminished superoxide MARKLUND, S.L., WESTMAN, N.G., LUND anion generation by reduced 5-imino GREN, E. & ROOS, G. (1982). Copper- and daunorubicin relative to daunorubicin and the zinc-containing superoxide dismutase, relationship to cardiotoxicity of the anthra manganese-containing superoxide dismutase, cycline antitumor agents. Biochemical Pharma catalase, and glutathione peroxidase in normal cology, 28, 2563. and neoplastic human cell lines and normal LOWN, ].W. (1982). Newer approaches to the cell tissues. Cancer Research, 42, 1955. study of the mechanisms of action of MASON, R.P. (1982). Free radical intermediates antitumor antibiotics. Accounts of Chemical in the metabolism of toxic chemicals. In Free Research, 15, 381. Radicals in Biology. Vol. V. Pryor (ed.), p. 161. LOWN, J.W., CHEN, H.-H., PLAMBECK, J.A. & Academic Press: New York. ACTON, E.M. (1982). Further studies on the MATHEWS, D.A., ALDEN, R.A., BOLIN, J.T. et generation of reactive oxygen species from al. (1978). Dihydrofolate reductase from Lacto activated anthracyclines and the relationship bacillus casei. Journal of Biological Chemistry, to cytotoxic action and cardiotoxic effects. 253, 6946. Biochemical Pharmacology, 31, 575. MELNYK, D.L., HORWITZ, S.B. & PEISACH, J. LOWN, J.W. (1983). The mechanism of action of (1981). Redox potential of iron-bleomycin. quinone antibiotics. Molecular and Cellular Biochemistry, 20, 5327. Biochemistry, 55, 17. METCALF, B.W., BEY, P., DANZIN, C. et al. LUMME, P. & KORVOLA, M.-L. (1975). Studies (1978). Catalytic irreversible inhibition of on coordination compounds. VI. Thermogravi mammalian ornithine decarboxylase (EC metric, differential thermogravimetric, 4.1.1.17) by substrate and product analogues. differential thermal analysis and mass spectro Journal of the American Chemical Society, 100, metric studies of some cobalt(II), nickel(II), and 2551. copper(II) salicylaldoximates, 2-indole MILLER, ].A. & MILLER, E.C. (1983). The carboxylates and 2-thiophenecarboxylates. metabolic activation and nucleic acid adducts Thermochimica Acta, 13, 419. of naturally-occurring carcinogens: recent LUMME, P., ELO, H. & ]ANNE, ]. (1984). results with ethyl carbamate and the spice Antitumor activity and metal complexes of the flavors safrole and estragole. British Journal of first transition series. Trans-bis(salicyl Cancer, 48, 1. aldoximato) copper(II) and related copper(II) MURRAY, D. & MEYN, R.E. (1985). DNA complexes, a novel group of potential anti damage in normal and neoplastic mouse tumor agents. Inorganica Chimica Acta, 92, 241. tissues after treatment with misonidazole in LUMME, P. & ELO, H. (1985). Antitumor activity vivo. Biochemical Pharmacology, 34, 3275 (and and metal complexes, a comparison. Inorganica references therin). Chimica Acta, 107, L15. NAGY, B., DALE, P.]., & GRDINA, D.]. (1986). CHARGE TRANSFER-OXY RADICAL MECHANISM 213
,. h Protection against cis-diamminedichloro- actions of carcinogens with nucleic acids. In Cancer 1. 2nd edn. Becker (ed.), p. 335££. ~i~~· b~ti~C~:~~~!d;,;u~r:~~J~:::~~fh!~l~~a~~!~ Plenum Press: New York. fr~:'\\,;: Research, 46, 1132. RAO, G.M., LOWN, J.W. & PLAMBECK, J.A. (1977a). Electrochemical studies of antitumor ~~: N~~z.A:3Sso~A, ~~:r~RGu~~RRii~~-~: antibiotics. I. Cyclic voltammetry study of '<;'' ".· (1985). Electrochemical and electron spin mitomycin B. Journal of the Electrochemical ~'?~~;~~>}; · resonance studies of actinomycin D and other Society, 124, 195. ,~: , . phenoxazones. Biophysical Chemistry, 21, 137. RAO, G.M., BEGLEITER, A., LOWN, J.W. & . NANDI, R. & MAITI, M. (1985). Binding of PLAMBECK, J.A. (1977b). Electrochemical stu ~';';i:;::: sanguinarine to deoxyribonucleic acids of dies of antitumor antibiotics. II. Polarographic ~h 0 ;L ·.· differing base composition. Biochemical Pharma and cyclic voltammetric studies of mitomycin ~r0i::::·.; co logy, 34, 321. C. Journal of the Electrochemical Society, 124, :t:;§.;:>NELSON, S.D. (1982). Metabolic activation and 199. ~~::[~:~;. drug toxicity. Journal of Medicinal Chemistry, RAO, G.M., LOWN, J.W. & PLAMBECK, J.A. {{;~1:·:·, 25, 753. (1978). Electrochemical studies of antitumor ;~:;;,,J <':~NETA, P., RICHOUX, M.-C. & HARRIMAN, A. antibiotics. III. Daunorubicin and adriamycin. :!f!s;i' i:< (1985). Intramolecular association of covalently Journal of the Electrochemical Society, 125, 534. · ,·, linked viologen radicals. Journal of the Chemical REICH, S.D. (1981). Other alkylating agents. In ::'' Society, Faraday Transactions 2, 81, 1427. Cancer and Chemotherapy, Antineoplastic Agents. :, ' OBERLEY, L.W. & BUETTNER, G.R. (1979). Role Vol. III. Crooke & Prestayko (eds), p. 61. ,;·,~\:>:~: . of superoxide dismutase in cancer: a review. Academic Press: New York. >";';)(] · Cancer Research, 39, 1141. REMY, J.J., BELEHRADEK, J. & JACQUEMINE Q.:~:,:·.~ OBERLEY, L.W., ROGERS, K.L., SCHUTT, L., SABLON, A. (1984). Expression of drug L,f~'::, OBERLEY, T.D., LEUTHAUSER, S.W.C., & sensitivity and tumorigenicity in intra-species SORENSON, J.R.J. (1983). Possible role of hybrids between 9-hydroxyellipticine ~";~;,_::.X·:<·, glutathione in the antitumor effect of a copper sensitive and -resistant cells. Cancer Research, ;;,.~· containing synthetic superoxide dismutase in 44, 4587. :~~,;~:;; mice. Journal of the National Cancer Institute, 71, ROBERTS, J.J. & THOMSON, A.J. (1979). The ~ttt' 1089. mechanism of action of antitumor platinum ~.,,;'OVERTON, M., HICKMAN, J.A., THREADGILL, compou,nds. Progress in Nucleic Acid Research 'rl>' · · M.D. et al. (1985). The generation of potentially and Molecular Biology, 22, 71. ROBINS, R.K. (1967). The purines and related ¥H;:;~ ·: :~!~b~~:~~v~/~:~~~:t~~n~ !:f~l t~~;;:u~~s~ ring systems. In Heterocyclic Compounds. Vol. ';i,·· .· .... Biochemical Pharmacology, 34, 2055. 8. Elderfield (ed.), pp. 356-357. Wiley: New :j::~·;'~~.-PAOLETTI, C., AUCLAIR, C. & MEUNIER, B. York. ·?~~:(:z·. (1983). Biochemical mechanisms of the cyto ROSENBERG, B. (1980). Platinum complexes for ·;~r:/1\•: toxic action of the antitumor ellipticine the treatment of cancer. In Nucleic Acid-Metal 1f't!)~~:T· derivatives. In Mechanism of Drug Action. Ion Interactions. Spiro (ed.), p. 1. Wiley-Inter science: New York. (eds), p. 305. J~~J~: ... ~~~::ni~;~:;s~rN:w ~~rtaza RYAN, M.D., SCAMEHORN, R.G. & KOVACIC, ~~~1.;:::JPARKANYI, C. & LEU, G.J. (1975). Charge P. (1985). Charge transfer in the mechanism of :~~~·~;'·.. transfer spectra of some heterocyclic cations. drug action involving quinoxaline di-N :::~~e?·r>; Zeitschrift fiir Naturforschung, 30b, 984. oxides. Journal of Pharmaceutical Sciences, 74, ;}~;j~'~ >~ETERING, D.H. (1972). The reaction of 3- 492. ;~};;,,~: 1 . ethoxy-2-oxobutyraldehyde bis (thiosemicar SADLER, P.J. (1982). Inorganic pharmacology . .·~J~k":·'; · bazonato) copper(II) with thiols. Bioinorganic Chemistry in Britain, 18, 182. ;~:I,,'/':: .Chemistry, 1, 273. SAENGER, W. (1984). Principles of Nucleic Acid ¥': ..;,,:,PETERING, D.H. (1980). Carcinostatic copper Structure. p. 201. Springer-Verlag: New York. ~~~}~·.: complexes. In Metal Ions in Biological Systems. SCHEULEN, M.E. & KAPPUS, H. (1984). The ~::;;;;}z. Vol. 11. Sigel (ed.), p. 197. Marcel Dekker: New activation of oxygen by bleomycin is catalyzed u:"···~. York. by NADPH-cytochrome P-450 reductase in the ;\,?12\(',PINTO, A.L. & LIPPARD, S.]. (1985). Binding of presence of iron ions and NADPH. In Oxygen ;~S.:';;.;: the antitumor drug cis-diamminedichloro Radicals in Chemistry and Biology. Bors, Saran & . :~~::, platinum(II) (cisplatin) to DNA. Biochimica et Tait (eds), p. 425. deGruyter: New York. ·\::,;)~> Biophysica Acta, 780, 167. SCOVILL, J.P., KLAYMAN, D.L. & 4'i:;&·~ RAJALAKSHMI, S., RAO, P.M. & SARMA, FRANCHINO. C.F. (1982). 2-Acetylpyridine ·.·;:.~ :. . D.S.R. (1982). Chemical carcinogenesis: inter- thiosemicarbazones. 4. Complexes with transi- 214 P. KOVACIC et al.
tion metals as antimalarial and antileukemic and hypoxic tumor cells. Cancer Research, agents. Journal of Medicinal Chemistry, 25, 1261. 73. SEIFTER, E., RETIURA, G., PADAWER, J. et al. • TSIFTSOGLOU, A.S., HWANG, K.M., (1984). Morbidity and mortality reduction by AGRAWAL, K.C. & SARTORELLI, A.C. (1975). supplemental vitamin A or {3-carotene in CBA Strand scission of sarcoma 180 tumor cell DNA mice given total-body y-radiation. Journal of induced by 1-formylisoquinoline thiosemi the National Cancer Institute, 73, 1167. carbazone. Biochemical Pharmacology, 24, 1631. SENGUPTA, S.K., KELLY, C. & SEHGAL, R.K. TS'O, P.O.P., CASPARY, W.J. & LORENTZEN, (1985). "Reverse" and "symmetrical" analogs R.J. (1977). The involvement of free radicals in of actinomycin D: metabolic activation and in chemical carcinogenesis. In Free Radicals in vitro and in vivo tumor growth inhibitory Biology. Vol. III. Pryor (ed.), p. 294. Academic activities. Journal of Medicinal Chemistry, 28, Press: New York. 620. WARBURG, 0., GAWEHN, K. & GEISSLER, SHERMAN, S.E., GIBSON, D., WANG, A.H.-J. & A.-W. (1957). The effect of hydrogen peroxide LIPPARD, S.J. (1985). X-ray structure of the on cancer cells and on embryonic cells. major adduct of the anticancer. drug cisplatin Zeitshrift fur Naturforschung, 12b, 393.
with DNA: cis-[Pt(NH3}z{d(pGpG)}]. Science, WARING, M.J. (1981). DNA modification and 230, 412. cancer. Annual Reviews of Biochemistry, 50, 159. SHOOTER, K.V. (1972). Some aspects of the WHEELER, O.H. (1963). Polarographic reduction interaction of carcinogenic and mutagenic of o-alkylnitrobenzenes. Canadian Journal agents with purines in nucleic acids. In The Chemistry, 41, 192. Purines-Theory and Experiment, The Jerusalem WILLET, W.C., POLK, B.F., UNDERWOOD, B.A. Symposia on Quantum Chemistry and Bio et al. (1984). Relation of serum vitamins A and chemistry. Vol. IV. Bergmann & Pullman (eds), E and carotenoids to the risk of cancer. The p. 509. The Israel Academy of Sciences and New England Journal of Medicine, 310, 430. Humanities: Jerusalem. WILLSON, R.L. (1983). Free radical repair SHOWALTER, H.D.H., FRY, D.W., LEOPOLD, mechanisms and the interactions of glutathi W.R., LOWN, J.W., PLAMBECK, J.A. & one and vitamins C and E. In Radioprotectors RESZKA, K. (1986). Design, biochemical and Anticarcinogens. Nygaard & Simic (eds), p. pharmacology, electrochemistry, and tumor 1. Academic Press: New York. biology of antitumor, anthrapyrazoles. Anti WINKELMANN, D.A., BERMKE, Y. Cancer Drug Design, 1, 73. PETERING, D.H., (1974). Comparative SIES, H. (ed.) (1985). In Oxidative Stress. properties of the antineoplastic agent, 3- Academic Press: New York. ethoxy-2-oxobutyraldehyde bis (thiosemicar SINHA, B.K. & CHIGNELL, C.F. (1979). Binding bazonato) copper(II) and related chelates: mode of chemically activated semiquinone free linear free energy correlations. Bioinorganic .radicals from quinone anticancer agents to Chemistry, 3, 261 . DNA. Chemico-Biological Interactions, 28, 301. YAO, T., WASA, T. & MUSHA, S. (1976). The SLAGA, T.J. (1983). Chemical carcinogenesis and electrochemical behavior of the purine bases anticarcinogenesis. In Radioprotectors and Anti and their nucleosides in N,N-dimethyl carcinogens. Nygaard & Simic (eds), p. 437. formamide. Nippon Kagaku Kaishi, 704; Academic Press: New York. Chemical Abstracts (1976), 85, 11616. STERN, A. (1985). Red cell oxidative damage. In YOUNGMAN, R.J., GOTZ, F. & ELSTNER, E.F. Oxidative Stress. Sies (ed.), pp. 340-341. (1984). Role of oxygen activation in Academic Press: New York. adriamycin-mediated DNA strand scission and SUGIHARA, K. & GEMBA, M. (1986). Modifica the effect of binding on the redox properties of tion of cisplatin toxicity by antioxidants. the drug. In Oxygen Radicals in Chemistry and Japanese Journal of Pharmacology, 40, 353; Biology. Bors, Saran & Tait (eds), p. 131. Chemical Abstracts (1986), 104, 81676. deGruyter: Berlin. TEICHER, B.A., LAZO, J.S. & SARTORELLI, A.C. ZUMAN, P. (1967). Substituent Effects in Organic (1981). Classification of antineoplastic agents Polarography. (a) p. 148, (b) p. 229. Plenum by their selective toxicities toward oxygenated Press: New York.