Incorporating Assessments of Sequence-Dependence in Developmental Studies of Combination Chemotherapy Regimens Containing New Agents and Platinum Compounds

  • Eric K. Rowinsky


The evaluation of combination chemotherapy regimens that incorporate new drugs has been accepted as the next rationale step in the development of new cytotoxic agents following the completion of phase I and early phase II trials. Before incorporating new agents into combination chemotherapy regimens, the new agent should have demonstrated a sufficient level of antitumor activity in relevant tumor types. In addition, adequate preclinical and clinical information about optimal scheduling should be available. New cytotoxic agents are often combined with platinum compounds, such as cisplatin and carboplatin, if the new agents possess relevant antitumor activity in ovarian, non-small and small cell lung, bladder, and germ cell carcinomas, as well as in other malignancies in which the platinum compounds are the mainstay of therapy.


Maximum Tolerate Dose Vinca Alkaloid Platinum Compound Sequence Iteration Combination Chemotherapy Regimen 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    E. Cadman, R. Heimer, L. Davis. Enhanced 5-fluorouracil nucleotide formation after methotrexate administration: explanation for drug synergism. Science 205:1135 (1979).CrossRefPubMedGoogle Scholar
  2. 2.
    C. Benz, E. Cadman E. Modulation of 5-fluorouracil metabolism and cytotoxicity by antimetabolite pretreatment in human colorectal adenocarcinoma HCT-8. Cancer Res. 41:994 (1981).PubMedGoogle Scholar
  3. 3.
    C. Benz, T. Tillis, E. Tattelman, E. Cadman. Optimal scheduling of methotrexate and 5-fluorouracil in human breast cancer. Cancer Res 42:2081 (1982).PubMedGoogle Scholar
  4. 4.
    N.E. Kemeny, T. Ahmed, R.A. Michaelson, H.D. Harper, L.C. Yip. Activity of sequential low dose methotrexate and 5-fluorouracil in advanced colorectal carcinoma: attempt at correlation with tissue and blood levels of phosphoribosylpyrophosphate. J Clin Oncol 2:311 (1984).PubMedGoogle Scholar
  5. 5.
    C. Benz, M. DeGregorio, S. Saks, et al. Sequential infusions of methotrexate and 5-fluorouracil in advanced cancer: pharmacology, toxicity, and response. Cancer Res 45:3354(1985).PubMedGoogle Scholar
  6. 6.
    J.L. Grem, C.J. Allegra. Sequence-dependent interactions of 5-fluorouracil and arabinosyl-5-azacytidine or 1-β-D-arabinfuranosylcytosine. Biochem Pharmacol 42:409 (1991).CrossRefPubMedGoogle Scholar
  7. 7.
    R.A. Bender, W.A. Bleyer, S.A Frisby. Alteration of methotrexate uptake in human leukemia cells by other agents. Cancer Res. 35:1305 (1975).PubMedGoogle Scholar
  8. 8.
    R.F. Zager, S.A. Frisby, V.T. Oliverio. The effects of antibiotics and cancer chemotherapeutic agents on the cellular transport and antitumor activity of methotrexate in L1210 murine leukemia. Cancer Res. 33:1670 (1993).Google Scholar
  9. 9.
    R.D. Warren, A.P. Nichols, R.A. Bender. The effect of vincristine on methotrexate uptake and inhibition of DNA synthesis by human lymphoblastoid cells. Cancer Res. 37: 2993 (1977).PubMedGoogle Scholar
  10. 10.
    R.A. Bender, A.P. Nichols, L. Norton, et al. Lack of therapeutic synergism of vincristine and methotrexate in L1210 murine leukemia in vivo. Cancer Treat. Rep. 62:997 (1978).PubMedGoogle Scholar
  11. 11.
    E.K. Rowinsky, R.C. Donehower, R. J. Jones, R.W. Tucker. Microtubule changes and cytotoxicity in leukemic cell lines treated with taxol. Cancer Res. 48:4093 (1988).PubMedGoogle Scholar
  12. 12.
    P. O’Connor, D. Ferris, G. White, et al. Relationship between cdc2 kinase activation, p34cdc2 dephosphorylation, and mitotic progression in Chinese hamster ovary cells exposed to etoposide. Cancer Res 52:1817 (1992).Google Scholar
  13. 13.
    J. Chou, P. Talalay. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs and enzyme inhibitors. Adv Enzyme Regul 22:27 (1984).CrossRefPubMedGoogle Scholar
  14. 14.
    A.H. Calvert, D.R. Newell, L.A. Gumbrell. et al. Carboplatin dosage: Prospective evaluation of a simple formula based on renal functions. J Clin Oncol 7:1748 (1989).PubMedGoogle Scholar
  15. 15.
    D.I. Jodrell, M.J. Egorin, RM. Canetta, et al. Relationships between carboplatin exposure and tumor response and toxicity in patients with ovarian cancer. J Clin Oncol 10:520, (1992).PubMedGoogle Scholar
  16. 16.
    E.K. Rowinsky, M. Gilbert, W.P. McGuire, et al. Sequences of taxol and cisplatin: a phase I and pharmacologic study. J Clin Oncol 9:1692 (1991).PubMedGoogle Scholar
  17. 17.
    E.K. Rowinsky, M. Citardi, D.A. Noe, R.C. Donehower: Sequence-dependent cytotoxicity between cisplatin and the antimicrotubule agents taxol and vincristine. J Can Res Clin Oncol 119:737 (1993).CrossRefGoogle Scholar
  18. 18.
    R.J. Parker, M.D. Dabholkar, K-B Lee, F. Bostoick-Burton, E. Reed. Taxol effect on cisplatin sensitivity and cisplatin cellular accumulation in human ovarian cancer cells. Monograph Natl Can. Inst. 15:83, (1993).Google Scholar
  19. 19.
    E. Reed, RJ. Parker, M. Dabholkar, et al. Taxol effect on cisplatin-DNA adduct repair in human ovarian cancer cells. (Abstract) Second National Cancer Institute Workshop on Taxol and Taxus. Alexandria, VA (1992).Google Scholar
  20. 20.
    G.A. LeBlanc, S.S. Sundseth, G.F. Weber, et al. Platinum anticancer drugs modulate P-450 mRNA levels and differentially alter hepatic drug and steroid hormone metabolism in male and female rats. Cancer Res 5:540, (1992).Google Scholar
  21. 21.
    L.J.C. van Warmerdam, M.T. Huizing, S. Rodenhuis, et al: Can the Calvert formula predict the pharmacokinetics of carboplatin (C) when C is given in combination with paclitaxel (P). (Abstract) 7th International Symposium on Platinum and other metal coordination compounds in Cancer Chemotherapy. Abstract Book S67, Amsterdam, The Netherlands (March 1–4, 1995).Google Scholar
  22. 22.
    W.P. McGuire, W.J. Hoskins, M.R. Brady, et al. A phase III trial comparing cisplatin/cytoxan (pc) and cisplatin/taxol (pc) in advanced ovarian cancer (aoc). (Abstract) Proc Am Soc Clin Oncol 12:255 (1993).Google Scholar
  23. 23.
    F.A. Holmes, D. Frye, V. Valero. et al. Phase I study of taxol and doxorubicin with G-CSF in patients without prior chemotherapy for metastatic breast cancer. (Abstract) Proc Am Soc Clin Oncol 11:600 (1992).Google Scholar
  24. 24.
    F.A. Holmes. Combination chemotherapy with Taxol (paclitaxel) in metastatic breast cancer. Ann Oncol 5(Suppl 6):S23–S27, 1994.PubMedGoogle Scholar
  25. 25.
    G.W. Sledge, N. Robert, J. Sparano, et al. Paclitaxel (Taxol)/doxorubicin combinations in advanced breast cancer. The Eastern Cooperative Oncology Group Experience. Sem Oncol 21(Suppl. 8):15 (1994).Google Scholar
  26. 26.
    M.J Kennedy, D. Armstrong, R. Donehower, et al. The hematologic toxicity of the taxol/cytoxan doublet is sequence-dependent. (Abstract) Proc Am Soc Clin Oncol 13:137, (1994).Google Scholar
  27. 27.
    E.K. Rowinsky (unpublished results).Google Scholar
  28. 28.
    L. Gianni, G. Straneo, F. Capri. et al: Optimal dose and sequence finding study of paclitaxel (P) by 3 h infusion with bolus doxorubicin (D) in untreated metastatic breast cancer patients (Pts). (Abstract) Proc Am Soc Clin Oncol 13:74 (1994).Google Scholar
  29. 29.
    J. Verweij, A.S.T. Planting, M.E.L. Van der Berg, et al: A phase I study of docetaxel (Taxotere) and cisplatin in patients with solid tumors. (Abstract) Proc Am Soc Clin Oncol 13:148, (1994).Google Scholar
  30. 30.
    E.J. Katz, J.S. Vick, K.M. Kling. et al. Effect of topoisomerase modulators on cisplatin cytotoxicity in human ovarian carcinoma cells. EurJ Cancer 26:724 (1990).Google Scholar
  31. 31.
    B. Drewinko, C. Green, T.L. Loo. Combination chemotherapy in vitro with cis-dichlorodiammineplatinum(II). Cancer Treat Rep 60:1619, (1976).PubMedGoogle Scholar
  32. 32.
    Y. Kano, K. Suzuki, M. Akutsu. et al. Effects of CPT-11 in combination with other anti-cancer agents in culture. Int J Cancer 50:604 (1992).CrossRefPubMedGoogle Scholar
  33. 33.
    R. Johnson, F. McCabe, Y. Yu. Combination regimens with topotecan in animal tumor models. (Abstract) Ann Oncol 3(suppl 1):85, (1992).Google Scholar
  34. 34.
    K. Itoh, M. Takada, S. Kudo, et al. Synergistic effects of CPT-11 and cisplatin or etoposideon human lung cancer cell lines demonstrated by continuous infusion. (Abstract) Proc Am Assoc Cancer Res 33:259, (1992).Google Scholar
  35. 35.
    B. Drewinko, T.L. Loo, and E.J. Freireich. Combination chemotherapy in vitro. III. BCNU. Cancer Treat Rep 63:373 (1979).PubMedGoogle Scholar
  36. 36.
    M. Oguro. A topoisomerase I inhibitor, CPT-11: Its enigmatic antitumor activity in combination with other agents in vitro. (Abstract) In: Proceedings of the Third Conference on Topoisomerases, p 35 (1990).Google Scholar
  37. 37.
    E. Rowinsky, L. Grochow, S. Kaufmann, et al. Sequence-dependent effects of topotecan and cisplatin in a phase I and pharmacokinetic study. (Abstract) Proc Am Soc Clin Oncol 13:142, (1994).Google Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Eric K. Rowinsky
    • 1
  1. 1.The Johns Hopkins Oncology CenterThe Johns Hopkins University School of MedicineBaltimoreUSA

Personalised recommendations