Adozelesin is a highly potent alkylating agent that undergoes binding in the minor groove of double-stranded DNA (ds-DNA) at A-T-rich sequences followed by covalent bonding with N-3 of adenine in preferred sequences. On the basis of its highpotency, broad-spectrum in vivo antitumor activity and its unique mechanism of action, adozelesin has entered clinical trial. We report herein the cytotoxicity for Chinese hamster ovary (CHO) cells of several agents, including antitumor drugs, combined with adozelesin. The additive, synergistic, or antagonistic nature of the combined drug effect was determined for most combinations using the median-effect principle. The results show that in experiments using DNA- and RNA-synthesis inhibitors, prior treatment with the DNA inhibitor aphidicolin did not affect the lethality of adozelesin. Therefore, ongoing DNA synthesis is not needed for adozelesin cytotoxicity. Combination with the RNA inhibitor cordycepin also did not affect adozelesin cytotoxicity. In experiments with alkylating agents, combinations of adozelesin with melphalan or cisplatin were usually additive or slightly synergistic. Adozelesin-tetraplatin combinations were synergistic at several different ratios of the two drugs, and depending on the schedule of exposure to drug. In experiments using methylxanthines, adozelesin combined synergistically with noncytotoxic doses of caffeine or pentoxifylline and resulted in several logs of increase in adozelesin cytotoxicity. In experiments with hypomethylating agents, adozelesin combined synergistically with 5-azacytidine (5-aza-CR) and 5-aza-2′-deoxycytidine (5-aza-2′-CdR). Combinations of adozelesin with tetraplatin or 5-ara-2′-CdR were also tested against B16 melanoma cells in vitro and were found to be additive and synergistic, respectively. The synergistic cytotoxicity to CHO cells of adozelesin combinations with tetraplatin, 5-aza-CR, or pentoxifylline was not due to increased adozelesin uptake or increased alkylation of DNA by adozelesin.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Aviado DM, Dettelbach HR (1984) Pharmacology of pentoxifylline, a hemorheologic agent used in the treatment of intermittent claudication. Angiology 35: 407
Ayash L, Korbut T, Herman TS, Teicher BA (1991) Combination of the minor groove binder U-73975 or the intercalator mitoxantrone with antitumor alkylating agents in MCF-7 or MCF-7/CP cells. Cancer Lett 61: 7
Bergerson RJ, Ingeno MJ (1987) Microbial iron chelator induced cell cycle synchronization in L1210 cells: potential in combination chemotherapy. Cancer Res 47: 6010
Bhuyan BK, Smith KS, Adams EG, Petzold GL, McGovren JP (1992) Lethality, DNA alkylation and cell cycle effects of adozelesin (U-73975) on rodent and human cells. Cancer Res 52: 5687
Bucher RW, Sutherland EW (1962) Adenosine 3′,5′-phosphate in biological materials. J Biol Chem 237: 1244
Burris H, Earhart R, Kuhn J, Shaffer D, Smith G, Weiss G, Kasunic D, Padbury G, Campbell L, Von Hoff D (1992) A phase I trial of adozelesin, a novel DNA sequence-specific alkylating agent. Proc Am Assoc Cancer Res 33: 520
Chang T-T, Gulati S, Chou T-C, Colvin M, Clarkson B (1987) Comparative cytotoxicity of various drug combinations for human leukemic cells and normal hematopoietic precursors. Cancer Res 47: 119
Chou T-C (1991) The median effect principle and the combination index for quantitation of synergism and antagonism. In: Chou, T-C, Rideout, DC (eds) Synergism and antagonism in chemotherapy. Academic Press, New York, p 61
Chou T-C, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enz Regul 22: 27
Chou T-C, Talalay P (1987) Application of the median effect principle for assessment of low-dose risk of carcinogens and for the quantitation of synergism and antagonism of chemotherapeutic agents. In: Harrap, KR, Connors, TA (eds) New avenues in developmental cancer chemotherapy. Academic Press, New York, p 38
D'Arpa P, Beardmore C, Liu LF (1990) Involvement of nucleic acid synthesis in cell killing mechanisms of topoisomerase poisons. Cancer Res 50: 6919
DeVita VT (1981) The consequences of the chemotherapy of Hodgkin's disease: the 10th Annual David A. Karnofsky Lecture. Cancer 47: 1
Dezube BJ, Eder JP, Pardee AB (1990) Phase I trial of escalating pentoxifylline dose with constant dose of thio-TEPA. Cancer Res 50: 6806
Dion MD, Hussey DH, Osborne JW (1989) The effect of pentoxifylline on early and late radiation injury following fractionated irradiation in C3H mice. Int J Radiat Oncol Biol Phys 17: 101
Fingert HJ, Chang JD, Pardee AB (1986) Cytotoxicity, cell cycle, and chromosomal effects of methylxanthines in human tumor cells treated with alkylating agents. Cancer Res 46: 2463.
Fingert HJ, Pu AT, Chen Z, George PB, Alley MC, Pardee AB (1988) In vivo and in vitro enhanced antitumor effects by pentoxifylline in human cancer cells treated with thio-TEPA. Cancer Res 48: 4375
Frei E, Cucchi CA, Rosowsky A, Tantravahi R, Bernal S, Ervin TJ, Ruprecht RM, Haseltine WA (1985) Alkylating agent resistance: in vitro studies with human cell lines. Proc Natl Acad Sci USA 82: 2158
Frost P, Abruzzese JL, Hunt BH, Lee D, Ellis M (1990) Synergistic cytotoxicity using 2′-deoxy-5-azacytidine and cisplatin or 4-hydroperoxy-cyclophosphamide with human tumor cells. Cancer Res 50: 4572
Holm C, Covey JM, Kerrigan D, Pommier Y (1989) Differential requirement of DNA replication for the cytoxicity of DNA topoisomerases I and II inhibitors in Chinese hamster DC3F cells. Cancer Res 49: 6365
Hurley LH, Reynolds VL, Swenson DH, Petzold GL, Scahill TA (1984) Reaction of the antitumor antibiotics CC-1065 with DNA: structure of a DNA adduct with DNA sequence specificity. Science 226: 843
Kelly RC, Gebhard I, Wicnienski N, Aristoff PA, Johnson PD, Martin DG (1987) Coupling of cyclopropapyrroloindole (CPI) derivatives. The preparation of CC-1065, ent-CC-1065 and analogs. J Am Chem Soc 109: 6837
Lau CC, Pardee AB (1982) Mechanism by which caffeine potentiates lethality of nitrogen mustard. Proc Natl Acad Sci USA 79: 2942
Levi V, Jacobson EL, Jacobson MK (1978) Inhibition of poly(ADP-ribose)polymerase by methylated xanthines and cytokinins. FEBS Lett 88: 144
Li LH, Wallace TL, DeKoning T, Warpehoski M, Kelly RC, Prairie MD, Krueger WC (1987) Structure and activity relationship of several CC-1065 analogs. Invest New Drugs 5: 329
Li LH, Kelly RC, Warpehoski MA, McGovren JP, Gebhard I, DeKoning TF (1991) Adozelesin, a selected lead among cyclopropapyrroloindole analogs of the DNA-binding antibiotic, CC-1065. Invest New Drugs 9: 137
Lidor YJ, Shpall EJ, Peters WP, Bast RC (1991) Synergistic cytotoxicity of different alkylating agents for epithelial ovarian cancer. Int J Cancer 49: 704
Lock RB (1992) Inhibition of p34cdc2 kinase activation, p34cdc2 tyrosine dephosphorylation and mitotic progression of CHO cells exposed to etoposide. Cancer Res 52: 1817
Loewe S (1953) The problem of synergism and antagonism of combined drugs. Arzneimittelforschung 3: 285
Martin DG, Chidester CG, Duchamp DJ, Mizsak SA (1980) Structure of CC-1065 (NSC 298223), a new antitumor antibiotic. J Antibiot 33: 902
McClay EF, Albright KD, Jones JA, Eastman A, Christen RD, Howell SB (1992) Modulation of cisplatin resistance in human malignant melanoma. Cancer Res 52: 6790
McGovren JP, Clarke GL, Pratt EA, DeKoning TF (1984) Preliminary toxicity studies with the DNA-binding antibiotic CC-1065. J antibiot 37: 63
O'Connor PM, Ferris DK, Pagano M, Draetta G, Pines J, Hunter T, Longo DL, Kohn KW (1993) G2 delay induced by nitrogen mustard in human cells affects cyclin A/CDK2 and cyclin B/cdc2 kinase activities differently. J Biol Chem 268: 8298
Santos GW, Tutschka PJ, Brookmeyer R, Saral R, Beschorner WE, Bias WB, Braine HG, Burns WH, Elfenbein GJ, Kaizer H, Mellits D, Sensenbrenner LL, Stuart RK, Yeager AM (1983) Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med 309: 1347
Schabel FM, Trader MW, Laster WR, Wheeler GP, Witt MH (1978) Patterns of resistance and therapeutic synergism among alkylating agents. In: Schabel FM (ed) Antibiotics and chemotherapy. S. Karger, Basel, p 200
Schabel FM, Griswold DP, Corbett TH, Laster WR (1983) Increasing therapeutic response rates to anticancer drugs by applying basic principles of pharmacology. Pharmacol Ther 20: 282
Shalinsky DR, Andreef M, Howell SB (1990) Modulation of drug sensitivity by dipyridamole in multidrug resistant tumor cells in vitro. Cancer Res 50: 7537
Shin C, Strayer JM, Wani MA, Snakpa RM (1990) Rapid evaluation of topoisomerase inhibitors: caffeine inhibition of topoisomerases in vivo. Teratogenesis, Carcinog Mutagen 10: 41
Smith KS, Folz B, Adams EG, Bhuyan BK (1992) 2-Drug combinations of the potent alkylating agent adozelesin. Proc Am Assoc Cancer Res 33: 440
Swenson D, Li AH, Hurley LH, Rokem JS, Petzold GL, Dayton BD, Wallace TL, Lin AH, Krueger WC (1982) Mechanism of interaction of CC-1065 with DNA. Cancer Res 42: 2821
Teicher BA, Cuechi CA, Lee JB, Flatow JL, Rosowsky A, Frei E (1986) Alkylating agents: in vitro studies of corss-resistance patterns in human tumor cell lines. Cancer Res 46: 4379
Teicher BA, Holden SA, Jones SM, Eder JP, Herman TS (1989) Influence of scheduling on two-drug combinations of alkylating agents in vivo. Cancer Chemother Pharmacol 25: 161
Teicher BA, Holden SA, Herman T-S, Epelbaum R, Pardee AB, Dezube B (1991) Efficacy of pentoxifylline as a modulator of alkylating agent activity in vitro and in vivo. Anticancer Res 11: 1555
Tsao Y, D'Arpa P, Liu LF (1992) The involvement of active DNA synthesis in camptothecin-induced G2 arrest: altered regulation of p34cdc2/cyclin B. Cancer Res 52: 1823
Vesely J (1982) Synergistic effect of cisplatin and 5-aza-2′-deoxycytidine on mouse leukemia cells in vivo and in vitro. Int J Cancer 29: 81
Warpehoski MA (1986) Total synthesis of U-71184, a potent new antitumor agent modeled on CC-1065. Tet Lett 27: 4103
Warpehoski MA, Gebhard I, Kelly RC, Krueger WC, Li LH, McGovren JP, Prairie MD, Wicnienski N, Wierenga W (1988) Stereoelectronic factors influencing the biological activity and DNA interaction of synthetic antitumor agents modeled on CC-1065. J Med Chem 31: 590.
Webb JL (1963) Effect of more than one inhibitor. Enzyme and metabolic inhibitors. Academic Press, New York, p. 66, 488.
Wolfrom DM, Rao AR, Welsch CW (1991) Caffeine inhibits development of benign mammary gland tumors in carcinogentreated female Sprague-Dawley rats. Breast Cancer Res Treat 19: 269
About this article
Cite this article
Smith, K.S., Folz, B.A., Adams, E.G. et al. Synergistic and additive combinations of several antitumor drugs and other agents with the potent alkylating agent adozelesin. Cancer Chemother. Pharmacol. 35, 471–482 (1995). https://doi.org/10.1007/BF00686831
- Azodelesin combinations
- Antitumor drugs
- other agents