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Cancer Chemotherapy and Pharmacology

, Volume 33, Issue 3, pp 245–250 | Cite as

Schedule-dependent synergism of edatrexate and cisplatin in combination in the A549 lung-cancer cell line as assessed by median-effect analysis

  • Edith A. Perez
  • Frank M. Hack
  • Lauri M. Webber
  • Ting-Chao Chou
Original Articles Edatrexate, Cisplatin, Median Effect, Analysis

Abstract

The methotrexate analog edatrexate has been shown to have greater antitumor activity and an improved therapeutic index as compared with its parent compound in preclinical systems. These studies suggest that edatrexate may have a broad role in the treatment of solid tumors. Information regarding edatrexate in combination with other chemotherapeutic agents is limited. We evaluated the interaction of edatrexate with cisplatin in vitro as assessed by median-effect analysis in the A549 human lung-cancer cell line. The effects of dose, exposure time, and schedule dependence were assessed. Cytotoxicity was evaluated using the tetrazolium-based colorimetric (MTT) assay. The inhibitory concentration producing 50% absorbance (IC50 for edatrexate with 1 h exposure was 1.4μM. For all combination experiments, the edatrexate dose was fixed at 0.2 μM (IC10) whereas cisplatin (CDDP) concentrations were varied for 1-, 3-, and 24-h exposures either before or after edatrexate treatment. Drug interactions were assessed using the combination-index method as defined by median-effect analysis. A synergistic interaction was documented in experiments when edatrexate was applied prior to CDDP (combination index, <1). The combination studies in which edatrexate was used prior to CDDP resulted in significant reduction of all three CDDP IC50 values: 1-h IC50, from 30.0 to 3.9 μM; 3-h IC50, from 21.3 to 1.4 μM; and 24-h IC50, from 1.7 to 0.03 μM. In contrast, synergism was not observed in experiments in which edatrexate treatment occurred after cisplatin exposure. Median-effect analysis is a useful method of determining drug interactions. In the present study, the combination of edatrexate and CDDP demonstrated schedule-dependent synergism, with the synergism being observed only in the setting of edatrexate treatment before CDDP exposure. Due to the potential broad spectrum of activity of edatrexate plus CDDP, further studies are warranted to determine the mechanism responsible for the synergism and to investigate this combination in a variety of tumor models.

Keywords

CDDP Combination Index Edatrexate Great Antitumor Activity Potential Broad Spectrum 
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.

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References

  1. 1.
    Alley MC, Scudiero DA, Monks A, Hursey ML, Czerwinski MJ, Fine DL, Abbott BJ, Mayo JG, Shoemaker RH, Boyd MR (1988) Feasibility of drug screening with panels of human tumor lines using a microculture tetrazolium assay. Cancer Res 48:589Google Scholar
  2. 2.
    Ayusawa D, Shimizu K, Koyama H, Takeishi K, Takeshi S (1983) Accumulation of DNA strand breaks during thymineless death in thymidylate synthase-negative mutants of mouse FM3A cells. J Biol Chem 258:12448Google Scholar
  3. 3.
    Berenbaum MC (1989) What is synergy? Pharmacol Rev 41:93Google Scholar
  4. 4.
    Chou J (1991) Quantitation of synergism and antagonism of two or more drugs by computerized analysis. In: Chou T-C, Rideout DC (eds) Synergism and antagonism in chemotherapy. Academic Press, San Diego, pp 223–244Google Scholar
  5. 5.
    Chou J, Chou T-C (1987) Dose-effect analysis with microcomputers: quantitation of ED50, LD50, synergism, antagonism, low-dose risk, receptor-ligand binding and enzyme kinetics. Manual and Software, Biosoft, Cambridge, EnglandGoogle Scholar
  6. 6.
    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, San Diego, pp 61–102Google Scholar
  7. 7.
    Chou T-C, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effect of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27Google Scholar
  8. 8.
    Chou T-C, Otter GM, Sirotnak FM (1993) Combined effects of edatrexate with taxol and toxotere against breast cancer cell growth. Proc Am Assoc Cancer Res 34:300Google Scholar
  9. 9.
    Chou T-C, Tan QH, Sirotnak FM (1993) Quantitation of edatrexate and cisplatin in vitro. Cancer Chemother Pharmacol 31:259Google Scholar
  10. 10.
    Feigal EG, Christian M, Cheson B, Grever M, Friedman M (1993) New chemotherapeutic agents in non-small cell lung cancer. Semin Oncol 20:185–201Google Scholar
  11. 11.
    Grant SC, Kris MG, Young CW, Sirotnak FM (1993) Edatrexate, an antifolate with antitumor activity: a review. Cancer Invest 11:36–45Google Scholar
  12. 12.
    Kris MG, Kinahan JJ, Gralla RJ, Fanucchi MP, Wertheim MS, O'Connell JP, Marks LD, Williams L, Farag F, Young CW (1988) Phase I trial and clinical pharmacological evaluation of 10-ethyl-10-deaza-aminopterin in adult patients with advanced cancer. Cancer Res 48:5573Google Scholar
  13. 13.
    Li JC, Kaminskas E (1984) Accumulation of DNA strand breaks and methotrexate cytotoxicity. Proc Natl Acad Sci USA 81:5694Google Scholar
  14. 14.
    Perez EA, Putney JD, Gandara DR (1989) In vitro dose-response relationship to cisplatin in human non-small cell lung cancer cell lines. Proc Am Assoc Cancer Res 30:459Google Scholar
  15. 15.
    Schmid FA, Sirotnak FM, Otter GM, DeGraw JI (1985) New folate analogs of the 10-deaza-aminopterin series: markedly increased antitumor activity of the 10-ethyl analog compared to the parent compound and methotrexate against some human tumor xenografts in nude mice. Cancer Treat Rep 69:551Google Scholar
  16. 16.
    Schmid FA, Sirotmak FM, Otter GM, DeGraw JI (1987) Combination chemotherapy with a new folate analog: activity of 10-ethyl-10-deaza-aminopterin compared to methotrexate with 5-fluorouracil and alkylating agents against advanced metastatic disease in murine tumor models. Cancer Treat Rep 71:727Google Scholar
  17. 17.
    Sedwick WD, Fyfe MJ, Brown OE, Frazer TA, Kutler M, Laszlo J (1979) Deoxyuridine incorporation as a useful measure of methotrexate and metoprine uptake and metabolic effectiveness. Mol Pharmacol 16:607Google Scholar
  18. 18.
    Sedwick WD, Kutler M, Brown OE (1981) Antifolate-induced misincorporation of deoxyuridine monophosphate into DNA: inhibition of high molecular weight DNA synthesis in human lymphoblastoid cells. Proc Natl Acad Sci USA 78:917Google Scholar
  19. 19.
    Shum KY, Kris MG, Gralla RJ, Burke MT, Marks LD, Heelan RT (1988) Phase II study of 10-ethyl-10-deaza-aminopterin in patients with stage III and IV non-small cell lung cancer. J Clin Oncol 6:446Google Scholar
  20. 20.
    Sirotnak FM (1980) Correlates of folate analog transport, pharmacokinetic and selective tumor action. Pharmacol Ther 8:71Google Scholar
  21. 21.
    Sirotnak FM, DeGraw JI, Moccio DM, Dorick DM (1982) Antitumor properties of a new folate analog, 10-deaza-aminopterin, in mice. Cancer Treat Rep 62:1047Google Scholar
  22. 22.
    Sirotnak FM, DeGraw JI, Moccio DM, Samuels LL, Goutas LJ (1984) New folate analogs of the 10-deaza-aminopterin series. Basis for structural design and biochemical and pharmacologic properties. Cancer Chemother Pharmacol 12:18Google Scholar
  23. 23.
    Sirotnak FM, DeGraw JI, Schmid FA, Goutas LJ, Moccio DM (1984) New folate analogs of the 10-deaza-aminopterin series: further evidence for markedly increased antitumor efficacy compared with methotrexate in ascitic and solid tumor models. Cancer Chemother Pharmacol 12:26Google Scholar
  24. 23a.
    Sirotnak FM, DeGraw JI, Schmid FA, Goutas LJ, Moccio DM (1984) New folate analogs of the 10-deaza-aminopterin series: basis for structural design and biochemical and pharmacologic properties. Cancer Chemother Pharmacol 12:18Google Scholar
  25. 24.
    Sirotnak FM, Schmid FA, DeGraw JI (1989) Intracavitary therapy of murine cancer withcis-diamminedichloroplatinum (II) and 10-ethyl-10-deaza-aminopterin incorporating systemic leucovorin protection. Cancer Res 49:2890Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • Edith A. Perez
    • 1
  • Frank M. Hack
    • 1
  • Lauri M. Webber
    • 1
  • Ting-Chao Chou
    • 2
  1. 1.Division of Hematology/OncologyUniversity of California, Davis, and Martinez VA Cancer CenterSacramentoUSA
  2. 2.Laboratory of Biochemical PharmacologyMemorial Sloan-Kettering Cancer CenterNew York

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