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Adozelesin, a potent new alkylating agent: cell-killing kinetics and cell-cycle effects

Summary

Adozelesin (U-73975) was highly cytotoxic to V79 cells in culture and was more cytotoxic than several clinically active antitumor drugs as determined in a human tumor-cloning assay. Phase-specificity studies showed that cells in the M + early G1 phase were most resistant to adozelesin and those in the late G1 + early S phase were most sensitive. Adozelesin transiently slowed cell progression through the S phase and then blocked cells in G2. Some cells escaped the G2 block and either divided or commenced a second round of DNA synthesis (without undergoing cytokinesis) to become tetraploid. Adozelesin inhibited DNA synthesis more than it did RNA or protein synthesis. However, the dose needed for inhibition of DNA synthesis was 10-fold that required for inhibition of L1210 cell growth. The observation that cell growth was inhibited at doses that did not cause significant inhibition of DNA synthesis and that cells were ultimately capable of completing two rounds of DNA synthesis in the presence of the drug suggests that adozelesin did not exert its cytotoxicity by significant inhibition of DNA synthesis. It is likely that adozelesin alkylates DNA at specific sites, which leads to transient inhibition of DNA synthesis and subsequent G2 blockade followed by a succession of events (polyploidy and unbalanced growth) that result in cell death.

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References

  1. 1.

    Adams EG, Crampton SL, Bhuyan BK (1981) Effect of 7-con-O-methylnogarol on DNA synthesis, survival and cell cycle progression of CHO cells. Cancer Res 41: 4981

  2. 2.

    Badiner GJ, Hamilton RD, Li LH, Bhuyan BK (1987) Drug sensitivity of ten human tumor cell lines compared to mouse leukemia (L1210) cells. Invest New Drugs 5: 219

  3. 3.

    Bhuyan BK, Groppi VE (1989) Cell cycle specific inhibitors. Pharmacol Ther 42: 307

  4. 4.

    Bhuyan BK, Newell KA, Crampton SL, Von Hoff DD (1982) CC-1065 (NSC 298223), a most potent antitumor agent: kinetics of inhibition of growth, DNA synthesis and cell survival. Cancer Res 42: 3532

  5. 5.

    Bhuyan BK, Crampton SL, Adams EG (1983) Cell cycle effects of CC-1065. Cancer Res 43: 4227

  6. 6.

    Chidester CG, Martin DG, Duchamp DJ, Mizsak SA (1980) Structure of CC-1065 (NSC 298223), a new antitumor antibiotic. J Antibiot 33: 902

  7. 7.

    Draetta G, Beach D (1988) Activation of cdc2 protein kinase during mitosis in human cells: cell cycle dependent phosphorylation and subunit rearrangement. Cell 54: 17

  8. 8.

    Gunji H, Khatbanda S, Kufe D (1991) Induction of internucleosomal DNA fragmentation in human myeloid leukemia cells by 1-β-d-arabinofuranosyl cytosine. Cancer Res 51: 741

  9. 9.

    Hurley LH, Reynolds VL, Swenson DH, Petzold GL, Scahill TA (1984) Reaction of the antitumor antibiotic CC-1065 with DNA: structure of a DNA adduct with DNA sequence specificity. Science 226: 843

  10. 10.

    Kelly RC, Gebhard I, Wicnienski N, Aristoff PA, Johnson PD, Martin DG (1987) Coupling of cycloproparyrroloindole (CPI) derivatives. The preparation of CC-1065, ent-CC-1065 and analogs. J Am Chem Soc 109: 6837

  11. 11.

    Kung AL, Sherwood SW, Schimke RT (1990) Cell line specific differences in the control of cell cycle progression in the absence of mitosis. Proc Natl Acad Sci USA 87: 9553

  12. 12.

    Li LH, Kuentzel SL, Murch LL, Pshigoda LM, Krueger WC (1979) Comparative biological and biochemical effects of nogalamycin and its analogs on L1210 leukemia. Cancer Res 39: 4816

  13. 13.

    Li LH, Wallace TL, DeKoning TF, Warpehoski MA, Kelly RC, Prairie MD, Krueger WC (1987) Structure and activity relationship of several CC-1065 analogs. Invest New Drugs 5: 329

  14. 14.

    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

  15. 15.

    Lock RB, Ross WE (1990) Inhibition of p34 cdc2 kinase activity by etoposide or irradiation as a mechanism of G2 arrest in CHO cells. Cancer Res 50: 3761

  16. 16.

    McGovren JP, Clarke GL, Pratt EA, DeKoning TF (1984) Preliminary toxicity studies with the DNA-binding antibiotic CC-1065. J Antibiot 37: 63

  17. 17.

    Smith KS, Adams EG, Von Hoff DD, Li LH, Wallace TL, Bhuyan BK (1989) Cell cycle effects of U-73975, a CC-1065 analog. Proc Am Assoc Cancer Res 21: 333

  18. 18.

    Sorensen CM, Barry MA, Eastman A (1990) Analysis of events associated with cell cycle arrest at G2 phase and cell death induced by cisplatin. J Natl Cancer Inst 82: 749

  19. 19.

    Swenson DH, Li LH, 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

  20. 20.

    Tobey RA, Crissman HA (1972) Use of flow microfluorimetry in detailed analysis of effects of chemical agents on cell cycle progression. Cancer Res 32: 2726

  21. 21.

    Von Hoff DD, Sanbach JF, Clark GM, Turner JN, Forseth BF, Piccart MJ, Colombo N, Muggia FM (1990) Selection of cancer chemotherapy for a patient by an in vitro assay vs a clinician. J Natl Cancer Inst 82: 110

  22. 22.

    Warpehoski MA (1986) Total synthesis of U-71 184, a potent new antitumor agent modeled on CC-1065. Tetrahedron Lett 27: 4103

  23. 23.

    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

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Correspondence to Bijoy K. Bhuyan.

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Bhuyan, B.K., Smith, K.S., Adams, E.G. et al. Adozelesin, a potent new alkylating agent: cell-killing kinetics and cell-cycle effects. Cancer Chemother. Pharmacol. 30, 348–354 (1992). https://doi.org/10.1007/BF00689961

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Keywords

  • Active Antitumor
  • Significant Inhibition
  • Specific Site
  • L1210 Cell
  • Alkylating Agent