Subject Index

A DNA binding 38-40 DNA strand breaks 37 Scatchard plot 36 ACIMBO 146 effects on nuclear nucleic acid 58 Aclacinomycin 59 and nuclear damage 36 Aclacinomycin A 60,63-5,67 Adriamycin macromolecule complexes and catalase 65,71 79 and DNA binding 64 Adriamycin-ara-C 106 and DNA strand breaks 64 Adriamycin-14-benzoate 94 and DNA synthesis 64 Adriamycin-14-(1-naphthalene acetate) and RNA synthesis 64 94 Acridine orange 2 Adriamycin-14-octanoate 94,120 Acridine yellow 3 Agglutination 25 Acridones 26-9 Aklavine 68 alkaloids 28 Aklavinone 59 nitroacridone 27 Albumin microspheres 79 thioacridone 27 Alcindromycin 66 Acriflavine 1, 2 Aldehyde reductase 109 Acrolein 11 0 Alkaline elution 37,206,316,318, Acronycine 28 335,336,344 and DNA synthesis 28 Alkaline sucrose sedimentation 206, detoxification 28 218,222,316,322 metabolism 28 Alkylated DNA 244 and RNA synthesis 28 Alkylated RNA 244 Actinomycins 24, 104, 148 Alkylating acridines 3, 4 inhibition of RNA synthesis 25 Alkylating agents 233ff, 284 Actinomycin D 37,104,129,150 local administration of 264 DNA damage 105 Alkylation of DNA bases 300 AD32 74,97,104 Alkylation products 300 cell cycle effects 74 7-a1kylguanines 300 AD41 97 Alkyltransferase 346,355 Adamanty1 substituents 385 Allopurinol 111 Adenocarcinoma 386 Ametantrone 82-5 Adriamycin 21,35-53,57-86,94, D-aminoacid oxidase 111 96, 104, 108 L-aminoacid oxidase 111 cardiotoxicity of 57 9-aminoacridine 1,18,22,23 chromatin binding 36-7 imino form 10 chromatin compaction 37 Aminopterin 368,380

395 396 Subject Index

AML 121 Ataxia telangiectasia 174 m-AMSA 12-21,37,104,105 Atebrin (see Mepacrine) antitumour spectrum 17 A V3 cells 212 cell division cycle 18 7-aza analogues 381 chromosomal aberrations 18 Azacrine 1 degradation 13 Aziridines 240, 249 DNA binding 14 Aziridinium ion 236 DNA damage 103 5-aziridino-2,4-dinitrobenzamide 272 DNA strand breaks 18 Aziridinyl quinone 326 DNA intercalation 14,18 1-aziridinyl-2,4-dinitrobenzene 250, equilibrium dialysis 20 251 immunosuppressive activity 17 Azo mustards 269, 270 irradiation 18 Azoreductase 268, 269 and leukaemia 17 and lymphoma 17 B mutagenic activity of 17 Scatchard plots 20 Bacteriophage 197 o-AMSA 16 T7 209 Amsacrine 12 Baker's soluble antifo1 385 log P values 12 Baker's triazinate 386 Angelicin 335 Base preference of saframycin Aniline mustard 247,265,274 binding 288 9-anilinoacridines 4, 9, 10-29 Base-propenals 163 and closed circular duplex DNA 12 BCND (see Chloroethylnitrosoureas) Hammett relationship 13 Bifunctional intercalation 129-33, 150 and intercalation with DNA 12, 14 and diacridines 24 pKa values 13 Bioreductive activation 293 and lipophilic-hydrophilic balance 12 Biotransformation of anthracycline 107 and petite mutants in yeast 16 Binding kinetics and diacridines 24 and QSARs 14,16 Bleomycin 157-78,184 X-ray crystallographic studies of 13 activated 169,170 Anthracyclines 286 and DNA damage 105 anaesthetic properties 113 and DNA strand breaks 165,166, biotransformation 107 174 immunosuppressive activity 95 and mutagenesis 176 neurotoxicity 113 Bleomycin-inactivating enzyme 177 reduction 111 Bleomycin-metal complexes 159 selective toxicity 95, 111 Blood-brain barrier 253 semiquinone radicals 111 Bohemic acid complex 65 structural relationships 59-63 N-bromoacetyl daunomycin 45 Anthramycin 288,290,301 5-bromo-2'-deoxyuridine 316 Anthranilic acid 269 7-bromomethylbenz(a)anthracene 222 Anthraquinones 81,84 Burkitt's lymphoma cells, DNA damage Antibacterial tests of TANDEM 130 and cytotoxicity 344 Antifol 363 Butyl ethers 242 Antitumour immunity and platinum drugs 191 c Apoptosis 106 Ara-C 106 Caffeine Arachidonic acid 116 inhibition of post replication repair, Arrhenius plots 148 337 Aryl-2-haloethyltriazenes 294 and toxicity of cis-DDP 217 Subject Index 397

Camptothecin 291 Chromomycin A3 297 Carboxypeptidase G 1 and metho• Chromophore resonances 44 trexate toxicity 369 Chromosome Carcinomycin (see 4-hydroxydauno• aberrations mycin) and aclacinomycin 63 Cardiac guany1ate cyclase, inhibition and m-AMSA 18 byanthracyclines 114 and bleomycin 175 Cardiomyopathy 35,95 breaks Carminic acid 85 and mitoxantrone 83 Carminomycin 59,78,94,102,108 and ametantrone 83 Carrier damage of methotrexate 368 staining of 7 protein, and alky1ating agent 276 Cinerubin A and B 65,67 transport 384 Circular dichroism 1 54 Carzinophilin A 303 cis-trans isomerisation 152 Catalase 116, 308 Citrovorum factor (see 5-formyl- and aclacinomycin A 65 tetrahydrofolic acid) CBDCA 263 Collinemycin 66 CCRF-CEM cells and 4-demethoxy• Colon tumour 350 daunomycin 97 Conformational calculations of dauno- Cell division mycin 46 and AD32 74 Cooperative binding 135, 136 and m-AMSA 18 Cooperative interaction 137 Cell survival and platinum compounds Cooperativity in dissociation 150 200 Cyclic AMP 368 CF (see 5-formy1tetrahydrofo1ic acid) Adriamycin, regulation by 114 Chelate effect 185 and platinum drugs 192 CHIP 201 Cyclic GMP regulation by Adriamycin Chlorambucil 234,237,247,274,276 114 Chlorasquin 382 Cyclic phosphodiesterases regulation Chlorocarcins 288 by Adriamycin 114 p-b is (2-chloroethyl)aminophenol 267 Cyclophosphamide 119,271,272, Ch10roethy1nitrosoureas (CNUS) 345 284,326 2-chloroethylnitrosoureas (CENU) Cytochrome P-450 110,170 284,295,303 reductase 108 1 ,3 -b is-( 2 chloroethyl)-l-nitrosourea Cytotoxicity (BCNU) 253, 254, 272, 284, of DNA damaging agents 352 306,355 of methotrexate 367 1-(2-chloroethyl)-1-nitrosourea (CNU) 356 1-(2-chloroethyl)-3-(trans-4-methyl• D cYclohexyl)-l-nitrosourea (MeCCNU) 253, 254 DAEP 385 bis(2-chloroethyl)sulphide 234 DAMP 385 Chlorozotocin 255, 351 Daunomycin 35-53,57-86,102,104, Chloroquine 273 111 CH NU 306 N-acetyl- 94, 97 Chromatin N-benzyl- 74 binding binding to with Adriamycin 36-7 chromatin 36-7 with daunomycin 36-7 DNA 38-40,46-8 compaction and Adriamycin 37 biotransformation 108 398 Subject Index

conformational calculations 46 crosslinking 8, 316 deoxy- 60 frequency of 318, 322 4-demethoxy- 94,97,102,104, resistance to agents 334 108 and platinum compounds 195 II-deoxy- 78 damage 163,323,339 dihydro- 59 and alky1ating agents 284-6 and DNA unwinding angle 40 and anthracyclines 103 6,11-di-o-methyl- 77 as a depot site 97 N,N-dibenzyl- 75 dissociation 146-7 N,N-dimethyl- 74 A-DNA 197 effects on nuclear nucleic acid 58 melting point of 40 4'-epi- 96 nuc1eosomal 103 and hydrogen-bonding interactions pSMl DNA 198 52 and platinum drugs, reaction with interaction with oligonucleotides 193ff 43,44 polymerase 99,216,328 NMR studies 43 protein crosslinks with 206, 208, polynucleotide interactions 45 319,337 quenching of fluorescence 38 replication, inhibition of 327 self-aggregation 43 strand breaks 166,174,292,303 structural studies 45-53 304,310,318,330,353 and tetranucleotide interaction 43 and AD32 74 toxicity 57 apurinic/apyrimidic sites 174 Daunomycin-dinucleoside complex and ac1acinomycin 64 42, 52 and m-AMSA 18 Daunomycin-hexamer structure 52 and bleomycin 165 Daunomycin-hexanucleotide complex and ethidium 36 41,44 and free radicals 307 Daunomycin-macromolecule studies and and mitoxantrone 83 nuclear damage 36 type 11 307 Daunomycin-oligonucleotide complex strand reassociation 316,321 50-3 structure 41 Daunomycinol 108 supercoiled CCC- 298 Daunomycinone 108 synthesis 174,366,387 Daunorubicin (see Daunomycin) and aclacinomycin A 64 Daunosamine sugar 38 and acronycine 28 I-and 3-deazamethotrexate 381,382 inhibition by anthracyclines of 98 3-deaza-trimethoprim 382 unwinding of 130,131 Density-hybrid method for measuring angle 23,24,26,40,132 DNA interstrand cross linking 316 viral 325 Deoxyribose cleavage by bleomycin Z-DNA 41 172 Deoxyuridy1ate 365 Deoxyribose nucleic acid (DNA) Depsipeptides 146 B-form 41,44,52,132 Depurination 299 binding 163, 173, 200 Depyrimidination 299 and aclacinomycin 64 Detoxification of acronycine 28 and Adriamycin 96 Diacridines 21-6, 129 and anthracyclines 96 bifunctional intercalation 24 and daunomycin 96 binding kinetics 24-5 and quinoxalines 129 mode of binding 22 closed circular duplex 12, 22, 131 and RNA synthesis 25 covalent bonding 10 Dialkyltriazenes 25 Subject Index 399

2,4-diamino-5-adamantyl-6-methyl• Dunning leukaemia ascites and di• pyrimidine 368 hydrotriazine 386 2, 4-diamino-5( 3,4-dichloropheny 1)- 6-methy1pyrimidine (DDMP or Metropine) 384 E 2,4-diamino-5,6-dihydro-6,6-di• Echinomycin 26, 127, 130-50 methyl-5-( 4' methoxypheny1)• binding to DNA s-triazine (MPT) 374 dissociation of 143-5 2,6-diaminopurine analogues 382 high affinity site of 142 cis-dichlorodiammine platinum (cis• preferred site of 142 DDP) 37,183-238,261,263, statistical mechanical model of 135 324,332,335,336,337,339, quinoline analogues of 130 352 Electric dichroism 22 trans-DDP 325,335 Electrophilic attack 301 cis-diammine-1 , 1-cyc1o butane dicarb- ELSERTA 146 oxy1ate platinum 11 (CBDCA) 263 Endonuc1eases, Mg2+ -Ca 2+ 105 1,2:5,6-dianhydro-D-mannito1 252 1,2: 5,6-dianhydrogalactito1 253 Epoxides 241 Dibromodu1cito1 252 Ethidium 14,19,26,131,133,297 Dibromomannito1 252 and DNA strand breaks 36 (J-diethy1aminoethy1dipheny1propy1- and DNA unwinding angle 40 acetate 110 Euflavine 1, 2 Difunctionality 244 Excision mechanisms 328,355 Dihydrofo1ate reductase 363-70, Exr gene 216 379,381,382 alterations in 370 F chickenliver 371,374,375,378,387 E. coli 371 Fanconi's anaemia 223,337 inhibition of 363 Fibre diffraction of daunomycin-DNA resistance, toxicity, pharmaco- complex 46 kinetics of 381 Filament formation, in bacteria 188 L. casei 370,371,377,383 Flow dichroism of steffimycin 72 mammalian 385 5-fluorodeoxyuridine monophosphate resistance 370 366-7 sequences of 371, 372 Fluorescence techniques and DNA of Streptococcus faecium, transport damage 297 of 364,368 F1uoroethyl nitrosoureas 350 Dihydrohomofolate 367 Folic acid inhibitors 363,365,379,380 Dihydrohomofolic acid 381 structure-activity relationships 380 Dihydrotriazine 371, 385 N1o-formyltetrahydrofolic acid 381 1-4-dimethanesu1phony1oxybutane 5-formy1tetrahydrofolic acid 368,369 253 Frameshift mutagens 4 N-N-dimethy1adriamycin 75 Free radicals 172, 173, 309, 310 5-(3,3-dimethy1-1-triazenohmidazo1e- Furocoumarins 325 4-carboxamide (DTIC) 256 Diphtheria toxin 276 Directed biosynthesis, of quinoxa1ine G analogues 129 Disulphide bond, chirality of 152 G1ucocorticoids 106 Diuresis 183 and DNA damage 105 L-dopa mustard Glucose oxidase Ill, 276 Doxorubicin (see Adriamycin) (J-Glucuronidase 265-7 400 Subject Index

Glutamate moiety modification in and m-AMSA 15,16,18,19 folic acid and methotrexate 383 and anthracyclines 96 r-Glutamyl transpeptidase 268 bifunctional 24,129-33,150 Glutathione and bleomycin 163,166,167 and m-AMSA degradation 13 and nitracrine 7 as cofactor for bleomycin 168 and psoralen 325 peroxidase 116 and quinoxalines 132,146,152 reductase 111,116 bis-intercalation 23-5, 129, 131, 135 Glycoaldehyde 111 Interstrand cross-linking 297,303, Glycosylase 221,329 318,325,330,343 activity 334 repair 328 Intrastrand crosslinks by platinum compounds 197,227 H Iremycin 80 e-Isorhodomycinone 80 Haloethylnitrosoureas 284 Hexamethylmelamine 258,259 analogues 260 Hexanucleotide and daunomycin interaction 44 L Histamine N-methyltransferase 385, 387 Lactic dehydrogenase 111 Hodgkin's disease 246 Ledakrin 6 p-hydroxyaniline mustard 265-7 Leucovorin (see 5-formyltetrahydro• 4-hydroxycyclophosphamide 271, 272 folic acid) 4-hydroxydaunomycin 45 L-leucyl daunomycin 75 Hydroxymalonatodiamine platinum (In Leukaemia 201 acute 386 7-hydroxymethotrexate 369 acute non-lymphocytic 106 Hydroxymethylpentamethylmelamine and m-AMSA 17 260 chronic myeloid 247 lymphatic 247 lymphocytic, I and Adriamycin and daunomycin 35 ICR compounds 3, 4 and methotrexate 363 and bifunctionality for DNA binding Linoleic acid 116 3 Lipid solubility of drugs 272 5-iminoadriamycin 77 Liver nuclei and biotransformation 5-iminodaunomycin 77 by Adriamycin and daunomycin Immune response effect of platinum 110 drugs 191 Lipoamide dehydrogenase 111 Induction of lysogeny, by platinum Liposome drugs 189 drug interactions with 115 Inhibitors, of dihydrofolate reductase phosphatidylcholine-liposomes 115 363-87 Lucanthone 37 Insertase enzyme 334 Lung cancer 246, 386 Intercalated ethidium 301 Lymphoma 246 his-intercalating ligand 22 and m-AMSA 17 Intercalation, with DNA Lymphosarcoma 246 and acridones 28 Lysosomes and Adriamycin release 79 and Adriamycin 37 Luzopeptin 129-32, 152 Subject Index 401

M Monoalkyltriazine 295 Morphological transformation and Malaria 1 DDP 190 Mannitol myleran 252, 253 MPT 374 Marcellomycin 66,67 Musettamycin 66,67 Melphalan 248, 274 Mustard gas 324 Membrane glycosylation and Adria• Mustards 333 mycin 114 Mutagenesis Membranes and m-AMSA 17 and Adriamycin 115 and bleomycin 176 and daunomycin 115 and DNA damaging agents 352 Mepacrine 3, 4 and ICR compounds 4 and neighbour exclusion model 22 and platinum complexes 192 Mer phenotype 348,352 Myleran 234, 253 Merophan 248 Metal-bleomycin complex 159 Metal sequestration 287, 296 Metaphase chromosomes 129 Methanesulfonyloxyalkanes 241, 252 N Methasquin 382 5,1 O-methenyltetrahydrofolic acid NADH-cytochrome c reductase III 379 NADH-oxidase, stimulation by Methotrexate 363,367,368,369,376, Adriamycin 114 378,379,380,383,385,387 NADPH 320,364,371,376 antileukaemic action of 363 ~-Naphthylamine 247 benzene ring of, substitution on 383 Naphthridinomycin 288 binding to dihydrofolate reductase Neighbour exclusion model 22,23, 370,376,377 150 halogen derivatives 383 Neocarzinostatin 164, 290 metabolism 369 and DNA damage 105 N10 substitution and analogues 383 Neothramycins A and B 290 Methyl CCNU 284 Nephrotoxicity of cisplatin 183 4'-O-methyladriamycin 76 Nitracrine 6-10 9-methylaminoacridine 23 iminoacridan form 10 4'-O-methyldaunomycin 76 immunosuppressive properties 6 Methylenetetrahydrofolate 366 intercalation with DNA 7, 9 9,10-methylnogalarol 69, 71, 72 mutagenic activity 7 5-methyltetrahydrofolic acid 368,369 and RNA synthesis 7 N-methyl-valine 138 Nitrate reductase III Metoprine 368,384 Nitroacridine 27 Minor groove intercalation of dauno• Nitrogen mustard 222,234,237,246, mycin-oligonucleotide complex 315,323,330,337 50 Nitrosoureas 105,253,254,272, Mithramycin 297 332,356 Mitochondria, toxicity of anthra• Nogalarols 70 cyclines to 116 Nogalamycin 59,60,68-71 Mitoclomine 248 Nuclear damage 36 Mitomycin 222, 252, 286, 294, 302, Nuclear magnetic resonance 43, 327,336,337 195,274 Mitoxantrone 82, 83 Nuclear Overhauser enhancement MNNG 346,348,353 studies 53 MNU 332,346 Nuclease 18 402 Subject Index

o Purine antimetabolite 251 Pyrido-pyrimidines 387 Occluded site-size 135 Pyrimethamine 368,384 Octadepsipeptide ring 127 2 -pyrimidinyl-p-[N ,N-bis(2 chloro• Octapeptide nucleus 140 propyl)aminobenzene) sulphon• 01ivomycin 297 amide 274 'One-arm mustard' 235 Pyrrolo( 1,4 )-benzodiazepinone 290 Oxidative metabolism 294 Pyrromycin 65,67 Oxiranes 241, 252 €-Pyrromycinone 59,60,65 Oxygen, and bleomycin-induced DNA degradation 168 Oxyradicals 108 Q lQN (see Echinomycin) 130 P 2QN (see Echinomycin) 130 Quantitative structure-activity Passive diffusion of small molecule relationships inhibitors 368,384 9-anilinoacridines 14 Pentamethylmelamine 266 anthracyclines 79 Pepleomycin 158 Quelamycin 78 Petite mutants in yeast and Quinacrine 273 9-anilinoacridines 16 Quinazoline analogues 382,387 p-phenylenediamine mustard 277 Quinoline 135 Pipobroman 249 chromophores 3 Piposulphan 249 pep tides 131 Phage inactivation model of effect of Quinomycins 127,128,132,138,139, DDP 213 146-8, 154 Phleomycin 157,158,166,167 Quinoxaline antibiotics 127, 128, 129 Phosphoramide mustard 271, 272 directed biosynthesis 129 Phosphotriesterases 244 interaction with DNA Physical distribution of drugs 272 and energy calculations 150 pKaofMPT 375 and kinetics 142,144,146,147 Platinum complexes (see also eis-DDP) Quinoxaline-2-carboxylic acid 127 261,332,335,352 eis-platinum (ll) diammine dichloride (see eis-DDP) R PM2 phage DNA 297,303 Poly rA 306 Radiosensitisers 251 Poly(dA-dT) 132,133,135,136-8, Rat liver microsomes 108 142,147,149 recgenes 216 Poly (dC-de) 132,133,135,142, Recombination 216 146,147 Recombination repair 217,336 Poly rA· poly rU 146 Renal toxicity of platinum drugs Polycythaemia 247 183 Postreplication repair 330,337 Repair defects 336 Prednimustine 248 'Rescue' techniques 369-70 Procarbazine 260, 261 Rhodirubins 66 Proflavine 1, 18 Rhodomycinone Protein phosphorylation and platinum a2- 80 drugs 192 €- 59,60, 73 Protozoa 1 28 1- 60,80 Psoralens 222,325,328,330,335 Ribonucleic acid (RNA) Pulmonary toxicity of bleomycin 177 A-form 42 Subject Index 403

messenger-RNA and dihydrofolate Sulphonamides 275 reductase 370 Sulphur mustard 234,246 polymerase 8,9,148,216 Sulphydry1s, stimulation of bleo- and AD32 74 mycins by 168 and Adriamycin 74, 99 Supercoiling, of DNA 138,140 and daunomycin 99 Superoxide dismutase 116,308 synthesis Suppressor cells, depression by DNA directed 129 aclacinomycin A 63 inhibition of 25, 28,64, 98 sym-trihydroxymethyltrimethyl• transfer-RNA melamine 260 binding of daunomycin to 42 Roseorubins 60 Rubidazone 79 T Rudolphomycin 66,67 T2 phage 323 S T4 DNA 288 T7 phage 324 Saframycins 288,294,301 Tallysomycin 158,167 Sarcoma virus 95 TANDEM 130-2,135-49,152,154 Scatchard plots [Ala3 , Ala7 ) TANDEM 132,136, and aclacinomycin A 64 153 and Adriamycin 36,38,67 crystal structure 152 and m-AMSA 20 Testicular cancer and platinum drugs and 10-descarboxymethylmarcello- 184 mycin 68 cis-tetrach1orodiammine platinum (IV) and 10-descarboxymethy1rudol- 261 phomycin 68 Tetrahydroacridine derivatives 9 and marcellomycin 68 Tetrahydrofolate 379 and musettamycin 68 des-N-tetramethyltriostin A (see and nogalamycin 71-2 TANDEM) and rudolphomycin 68 Tetramin 250 and quinoxalines 133-7 Tetranucleotide Schiff base 307 helix-coil transition 43 Selective inhibitors of dihydrofolate interaction with daunomycin 43 reductases 370 Thioacetal crossbridge of quinomycins Semiquinone radicals 109 127,128,148 Sequence selectivity and amino acid Thioacridone 27 replacements 138,142 Thiotepa 234 Sister-chromatid exchange 83,176, 356 Thymidine 366,369 SKF 52A 110 Thymidylate synthetase 365-7,382 Spin-trapping 308 a-Tocopherol 116 Steffimycin 59,60, 72 Tomaymycin 290 Streptomyces Topoisomerase enzymes 37, 298 nogalater 68 Trans effect of platinum compounds peucetius 35 186 verticillus 157 Triazeneimidazoles 256 Streptonigrin 287,296 Triazenes 255,256,284,295 Streptozotocin 255 aryl triazenes 257,258 Structure-activity relationships imidazole 28 of platinum compounds 186 2,3,4-triethyleneiminobenzoquinone of quinoxaline-DNA binding 137 (Trenimon) 256 Sulphadiazine 274-5 Triethylenemelamine (TEM) 246,259 404 Subject Index Triethy1enethiophosphoramide (thio• v TEPA) 249 N-trifluoroacety1-adriamycin-14- Vinblastine 184 valerate 94 Vincristine 178 Trimethoprim 370,382 Vio1amycins 189 Triostin A 132,139,141,146,147 Viral inactivation by platinum com• halogenated derivatives of 138-41 pounds 189 Triostin C 132,146-8,150 Triptolide 241 W,X, Y Tumorigenesis 95 Tumour Walker 256 tumour 267 cell sensitivity 339 cells 345 pH 274 Xanthine 111 tissues 368 Xanthine oxidase and biotransforma• xenografts 259 tion of anthracyclines 110 Xeroderma pigmentosum 223,336,355 u X-ray crysta110graphy of daunomycin-hexanudeotide Ubiquinone 116 complex 50 Unwinding angle of DNA 23,24,26, of TANDEM 130,153 40,131-2 Urethane mustard 273 Yeast 333,357