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Activation of Adriamycin by the Ph-Dependent Formaldehyde- Releasing Prodrug Hexamethylenetetramine1

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Activation of Adriamycin by the Ph-Dependent Formaldehyde- Releasing Prodrug Hexamethylenetetramine1 Vol. 2, 189–198, February 2003 Molecular Cancer Therapeutics 189 Activation of Adriamycin by the pH-dependent Formaldehyde- releasing Prodrug Hexamethylenetetramine1 Lonnie P. Swift, Suzanne M. Cutts, Ada Rephaeli, factors, including a dose-limiting cardiotoxicity and MDR3 (1, Abraham Nudelman, and Don R. Phillips2 2). Adriamycin undergoes metabolic reduction and in the Department of Biochemistry, La Trobe University, Bundoora, Victoria presence of oxygen leads to the production of reactive ox- 3086, Australia [L. P. S., S. M. C., D. R. P.]; Felsenstein Medical ygen species (3, 4), and these species are particularly dam- Research Center, Sackler School of Medicine, Tel Aviv University, Beilinson Campus, Petach Tikva 49100, Israel [A. R.]; and Chemistry aging to cardiac tissue that do not possess enzymes to Department, Bar Ilan University, Ramat Gan 52900, Israel [A. N.] detoxify the resulting radicals (1). MDR occurs as a result of up-regulation of the membrane-associated P-glycopro- tein efflux pump (5). MDR therefore results in a diminished Abstract response to anthracycline anticancer agents such as Previous studies have shown that Adriamycin can Adriamycin. react with formaldehyde to yield an activated form The mechanism of action of Adriamycin and other anthra- of Adriamycin that can further react with DNA cyclines appears to involve impairment of topoisomerase II to yield Adriamycin-DNA adducts. Because activity (6–10) as well as the formation of DNA adducts hexamethylenetetramine (HMTA) is known to hydrolyze (11–14). Initial investigations of Adriamycin-DNA adducts us- under cellular conditions and release six molecules of ing an in vitro transcription footprinting assay suggested that formaldehyde in a pH-dependent manner, we examined the formation of adducts was enhanced in the presence of this clinical agent for its potential as a formaldehyde- iron (11). However, it was later shown that the Fe(III)/DTT/Tris releasing prodrug for the activation of Adriamycin. In buffer resulted in the production of formaldehyde that me- IMR-32 neuroblastoma cells in culture, increasing diated the formation of the drug-DNA adducts (3). levels of HMTA resulted in enhanced levels of Following the realization that formaldehyde mediated the Adriamycin-DNA adducts. These adducts were formed formation of Adriamycin-DNA adducts, studies were under- in a pH-dependent manner, with 4-fold more detected taken to fully understand this drug-DNA interaction in vitro.It at pH 6.5 compared with pH 7.4, consistent with the has been shown that formaldehyde supplies a methylene known acid lability of HMTA. The resulting drug-DNA group that links the 3Ј amino of Adriamycin to the 2-amino of lesion was shown to be cytotoxic, with combined deoxyguanosine residues of DNA via Schiff base chemistry Adriamycin and prodrug treatment resulting in a 3-fold (3, 13–16) and that the formaldehyde-conjugated complex is lower IC50 value compared with that of Adriamycin the active form of the drug (17). Although the adducts are alone. Given the acidic nature of solid tumors and the attached covalently to only one strand of DNA and are there- preferential release of formaldehyde from HMTA in fore mono-adducts, they stabilize the local region of DNA acidic environments, HMTA therefore has some sufficiently that they are resistant to thermal denaturation potential for localized activation of Adriamycin in solid and can therefore be detected in denaturation-based cross- tumors. linking assays (12–14, 17). It has been demonstrated that the presence of the amino group on the sugar moiety is critically Introduction important for the formation and stabilization of the drug-DNA Chemotherapeutic drugs are important in most types of cur- interaction (18–20). A preactivated form of Adriamycin rent cancer treatment protocols. One of the most widely (doxoform) has been shown to be taken up by cells at an used agents, Adriamycin (doxorubicin), exhibits a wide ac- accelerated rate, is retained longer in the nucleus, and is tivity against leukemias and breast, lung, thyroid, and ovarian substantially more cytotoxic than Adriamycin (21). carcinomas, as well as Hodgkin’s and non-Hodgkin’s lym- An alternative approach to enhance the activity of Adria- phomas (1, 2). Despite the remarkable efficiency with which mycin is to increase the intracellular level of formaldehyde, Adriamycin kills cells, treatment is complicated by many leading to enhanced formation of Adriamycin-DNA lesions. This approach has been investigated recently using a com- bination of Adriamycin and the formaldehyde-releasing pro- drug pivaloyloxymethyl butyrate (AN-9; Ref. 22). The prodrug is cleaved intracellularly by esterases, liberating formalde- Received 3/6/02; revised 8/12/02; accepted 11/27/02. hyde, which reacts with Adriamycin and results in a dramatic The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked increase of the number of Adriamycin-DNA adducts, to- advertisement in accordance with 18 U.S.C. Section 1734 solely to indi- cate this fact. 1 Supported by the Australian Research Council (D. R. P. and S. M. C.), La Trobe University Postgraduate Scholarship (to L. P. S.), The Marcus Center for Pharmaceutical and Medicinal Chemistry, and the Bronia and Samuel 3 The abbreviations used are: MDR, multidrug resistance; HMTA, hexa- Hacker Fund for Scientific Instrumentation at Bar Ilan University (A. N.). methylenetetramine; TE, 10 mM Tris (pH 8)-1 mM EDTA; mtDNA, mito- 2 To whom requests for reprints should be addressed. E-mail: chondrial DNA; DHFR, dihydrofolate reductase; dsDNA, double-stranded [email protected]. DNA; ssDNA, single-stranded DNA. Downloaded from mct.aacrjournals.org on October 1, 2021. © 2003 American Association for Cancer Research. 190 Activation of Adriamycin by HMTA gether with a synergistic cytotoxic response. However, AN-9 Worthington Chemical Corp. Tris-saturated ultrapure phenol also releases butyric acid, which inhibits histone deacetylase was purchased from Life Technologies, Inc., and formalde- and, as such, potentially modulates the chromatin accessi- hyde was purchased from BDH. ProbeQuant G-50 columns, bility of Adriamycin, thus contributing to the observed syn- [␣- 32P]dCTP, [␣- 32P]dATP, [␣- 32P]UTP (3000 Ci/mmol) and ergistic response. [14-14C]Adriamycin hydrochloride were obtained from Am- HMTA is a tertiary amine that hydrolyzes under acidic ersham Pharmacia Biotech. The plasmid containing the conditions to yield ammonia and formaldehyde (23). We have DHFR probe, pBH31R1.8 (36), was a gift from Dr. V. A. Bohr therefore examined it as a pH-dependent formaldehyde- (National Institute on Aging, NIH, Baltimore, MD), whereas releasing prodrug, thus enabling us to study the effects of the plasmid with a mitochondrial insert (pCRII-H1) was a gift formaldehyde release independently of butyric acid release. from Dr. C. A. Filburn (National Institute on Aging, NIH). HMTA has been examined as an antiseptic for the treatment Qiagen Plasmid Maxi Kits and QIAamp blood kit were from of urinary tract infections (24), as well as being studied in Qiagen. The Klenow fragment of DNA polymerase, glycogen, patients with maxillofacial phelegmons (25) and as a prophy- and the random primed labeling kit were from Roche Molec- lactic agent against recurrent acute cystitis (26). It has also ular Biosciences. Lambda exonuclease was purchased from been tested in water systems at a concentration of 1 mg/liter Life Technologies, Inc. All other enzymes were purchased (27) for its antiseptic properties (25). It is particularly well from New England Biolabs. tolerated by humans, even at high doses of up to 5 g/kg/day (28). The degradation of HMTA produces six molecules of Methods formaldehyde for every molecule of drug hydrolyzed, sug- In Vitro Detection of Drug-DNA Adducts. The plasmid gesting that it may be a more efficient prodrug than AN-9, pCCI (37) was linearized with HindIII and end-labeled with which releases only one molecule of formaldehyde when [␣-32P]dCTP or [␣-32P]dATP in the presence of the Klenow degraded by esterases (29). fragment of Escherichia coli DNA polymerase I. Unincorpo- Warburg (30) suggested that tumors were acidic because rated label was removed using G-50 ProbeQuant columns. of the production of lactic acid, due to the metabolism of The labeled DNA was resuspended in calf thymus DNA to a tumor cells in an anaerobic environment. However, more final concentration of 400 ␮⌴ bp in TE buffer. recently it has been shown that the intracellular pH in tumors End-labeled DNA (25 ␮M bp) was reacted with drugs at tends more toward neutral or alkaline values (31, 32), 37°C for defined times in PBS (adjusted to the desired pH). whereas the extracellular pH was shown to be acidic (33–35). Unreacted drugs were extracted with phenol and chloroform, Due to the acidic extracellular pH of solid tumors, it would be and the DNA was precipitated in ethanol (using glycogen as expected that HMTA would be preferentially hydrolyzed to an inert carrier). The pellet was washed with 70% ethanol, release formaldehyde in the tissues adjacent to such tumors. dried, and resuspended in TE. Samples were denatured in a It has been shown that the dose of Adriamycin required to final concentration of 66% loading dye (60% formamide, 6.6 induce a cytotoxic response can be diminished when coad- mM EDTA, 0.07% xylene cyanol, and 0.07% bromphenol ministered with a formaldehyde-releasing prodrug (22). It blue) at 65°C for 5 min. Samples were quenched on ice and was therefore expected that a similar response would also be then loaded onto a 0.8% agarose gel (40 cm), and the DNA achieved with the coadministration of HMTA with Adriamy- was separated electrophoretically in TAE buffer [40 mM Tris- cin. Moreover, the fact that formaldehyde is released from acetate, 1 mM EDTA (pH 8.0)] at 45 V for 16 h.
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