Skip to main content
SpringerLink
Log in

Schedule-dependent synergism of taxol or taxotere with edatrexate against human breast cancer cells in vitro

  • Edatrexate, Taxol, Taxotere, Breast Cancer, Combination Treatment
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

A new dihydrofolate reductase inhibitor, edatrexate (EDX), and the microtubule polymerization promotor, taxol (TXL) or taxotere (TXT), each have significant therapeutic activity against human breast cancer in clinical trials. Since they also have distinctly different mechanisms of actions and have mainly nonoverlapping toxicities, they may be effective in combination in the treatment of this disorder. Schedule-dependent interactions between these taxanes and EDX against human breast adenocarcinoma cells (SK-Br-3) were quantitatively assessed in vitro to determine whether these interactions are synergistic or antagonistic. SK-Br-3 cells were grown as a monolayer in 96-well microplates. The dose-effect relationships of the drugs, singly and in combination, in inhibiting the growth over a 7-day period were determined by the SRB protein staining assays. Cell cultures were exposed to drug as a 3-h pulse at either 0–3 h or 24–27 h. Synergism or antagonism at different concentrations and at different effect levels were assessed with the medianeffect principle and the combination index-isobologram method using computer software. These methods were selected because they take into account both the potencies and the shape of the dose-effect curves. Exposure of cells to an equimolar combination of EDX+TXL (0–3 h) resulted in synergism at high effect levels. Pretreatment of cells with EDX (0–3 h) followed by TXL (24–27 h) showed even greater synergism in inhibiting cell growth. Moderate antagonism was observed with the reverse schedule. EDX+TXT (0–3 h) was additive, but pretreatment with EDX (0–3 hr) followed by TXT (24–27 h) showed synergism. However, the reverse order showed antagonism. Studies on another breast tumor cell line, ZR-57-1, also showed the schedule of EDX (0–3 h) +TXT or TXL (24–27 h) to be more synergistic than, the other two schedules examined. These results show potent schedule-dependent synergism of the combinations of TXL or TXT with EDX, and should form a rationale for designing clinical protocols utilizing these agents particularly for the treatment of breast cancer patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

TXL :

taxol

TXT :

taxotere

EDX :

10-ethyl-10-deaza-aminopterin

CI :

combination index

DRI :

dose-reduction index

References

  1. Horwitz SB (1992) Mechanism of action of taxol. Trends Pharmacol Sci 13: 134–136

    Google Scholar 

  2. Bissery MC, Guenard D, Voegelein-Gueritte F, Lavelle F (1989) Experimental antitumor activity of taxotere (RP 56976, NSC 628503), a taxol analogue. Cancer Res 51: 4845–4852

    Google Scholar 

  3. Schiff PB, Horwitz SB (1980) Taxol stabilizes microtubules in mouse fibroblasts cells. Proc Natl Acad Sci USA 77: 1561–1565

    Google Scholar 

  4. Horwitz SB, Lothstein L, Manfredi JJ, et al (1986) Taxol: mechanisms of action and resistance. Ann NY Acad Sci 466: 733–744

    Google Scholar 

  5. Kris MG, O'Connell JP, Gralla RJ, et al (1986) Phase I trial of taxol given as a 3-hour infusion every 21 days. Cancer Treat Rep 70: 605–607

    Google Scholar 

  6. National Cancer Institute (1990) Clinical brochure (revised): taxol IND 22850 NSC 125973. Division of Cancer Treatment, NCI, Bethesda, 10–17 August

    Google Scholar 

  7. Slichenmyer WJ, VonHoff DD (1991) Taxol, a new and effective anticancer drug. Anti-cancer drugs 2: 519–530

    Google Scholar 

  8. Sirotnak FM, Schmid FA, Samuels LL, DeGraw JI (1987) 10-Ethyl-10-deaza-aminopterin: structural design and biochemical, pharmacologic, and antitumor properties of folates and folic acid antagonists in cancer chemotherapy. NCI Monogr 5: 127–131

    Google Scholar 

  9. 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 murine tumor models. Cancer Chemother Pharmacol 12: 26–30

    Google Scholar 

  10. Schmid FA, Sirotnak FM, Otter GM, DeGraw JI (1985) New folate analogs of the 10-deazaaminopterin 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: 551–553

    Google Scholar 

  11. Grant SC, Kris MG, Young CW, Sirotnak FM (1993) Edatrexate, an antifolate with antitumor activity: a review. Cancer Invest 11: 36–45

    Google Scholar 

  12. Kris MG, Kinahan JJ, Gralla RJ, Fanucchi MP, Weitheim MS, O'Connell JP, Marks LD, William L, Farag F, Young CW, Sirotnak FM (1988) Phase I trial and clinical pharmacological evaluation of 10-ethyl-10-deazaminopterin in adult patients with advanced cancer. Cancer Res 48: 5573–5579

    Google Scholar 

  13. Shum KY, Kris MG, Gralla RJ, Burke MT, Marks LD, Heeland RT (1988) Phase II study of 10-ethyl-10-deaza-aminopterin in patients with stage II and IV non-small cell lung cancer. J Clin Oncol 6: 446–450

    Google Scholar 

  14. Lee JS, Libshitz MI, Murphy WK, et al (1990) Phase II study of 10-ethyl-10-deaza-aminopterin (10-EDAM: CGP 30694) for stage II B or IV non-small cell lung cancer. Invest New Drugs 8: 299–304

    Google Scholar 

  15. Schornagel JH, Vegt S van der, deGraeff A, Dullemond-Westlan A, vanDeijk WA, TenBokked Huinink WW (1992) Phase II study of edatrexate in chemotherapy-naive patients with metastatic breast cancer. Ann Oncol 3: 549–552

    Google Scholar 

  16. Vandenberg TA, Pritchard KI, Eisenhauer EA, Trudeau ME, Norris BD, Lopez P, Verma SS, Burckman RA, Muldal A (1993) Phase II study of weekly edatrexate as first-line chemotherapy for metastatic breast cancer: National Cancer Institute of Canada clinical trials group study. J Clin Oncol 11: 1241–1244

    Google Scholar 

  17. Schmid FA, Sirotnak FM, Otter GM, DeGraw JI (1987) Combination chemotherapy with a new folate analog: activity of 10-ethyl-10-deazaminopterin compared to methotrexate with 5-fluorouracil and alkylating agents against advanced metastatic disease in murine tumor models. Cancer Treat Rep 71: 727–732

    Google Scholar 

  18. Sirotnak FM, Schmid FA, Degraw JI (1989) Intracavitary therapy of murine ovarian cancer with Cis-diaminodichloroplatinum (II) and 10-ethyl-10-deaza-aminopterin incorporating systemic leucovorin protection. Cancer Res 49: 2890–2893

    Google Scholar 

  19. Otter GM, Sirotnak FM (1994) Effective combination therapy of metastatic murine solid tumors with edatrexate and vinca alkaloids, vinblastine, navelbine and vindesine. Cancer Chemother Pharmacol 33: 286–290

    Google Scholar 

  20. Chou T-C, Talalay P (1981) Generalized equations for the analysis of inhibitors of Michaelis-Menten and higher order kinetic systems with two or more mutually exclusive and nonexclusive inhibitors. Eur J Biochem 115: 207–216

    Google Scholar 

  21. Chou T-C, Talalay P (1987) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22: 27–55

    Google Scholar 

  22. Chou T-C, Talalay P (1987) Applications of the median-effect principle for the 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. (Bristol-Myers Symposium series) Academic Press, New York, pp 37–64

    Google Scholar 

  23. Chou T-C (1991) The median-effect principle and the combination index for quantitation of synergism and antagonism. In: Chou T-C Rideout D (eds) Synergism and Antagonism in Chemotherapy. Academic Press, New York, pp 61–102

    Google Scholar 

  24. Chou T-C, Tan Q-H, Sirotnak FM (1993) Quantitation of the synergistic interaction of edatrexate and cisplatin in vitro. Cancer Chemother. Pharmacol 31: 259–264

    Google Scholar 

  25. Perez EZ, Hack FM, Webber LM, Chou T.-C (1993) Schedule dependent synergism of edatrexate and cisplatin combination in the A549 lung cancer cell lines as assessed by median effect analysis. Cancer Chemother Pharmacol 33: 245–250

    Google Scholar 

  26. Lee JS, Libshity HL, Fassella FV, Murphy WK, Pang AC, Lippman SM, Dong MS, Dimery IW, Glisson BS, Hong KH (1992) Improved therapeutic index by leucovorin of edatrexate, cyclophosphamide and cisplatinum regimen for nonsmall cell lung cancer. J Natl Cancer Inst 84: 1039–1040

    Google Scholar 

  27. 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, UK

    Google Scholar 

  28. 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, New York, pp 223–244

    Google Scholar 

  29. Skehan P, Storeny R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenny S, Boyd MR (1990) New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 82: 1107–1112

    Google Scholar 

  30. Seidman AD (1994) Single-agent use of taxol (paclitaxel) in breast cancer. Ann Oncol 5: S17-S22

    Google Scholar 

  31. Reichman B S, Seidman A D, Crown J P A, Heelan R, et al (1993) Paclitaxel and recombinant human granulocyte colony-stimulating factor as initial chemotherapy for metastatic breast cancer. J Clin Oncol 11: 1943–1951

    Google Scholar 

  32. Seidman AD, Norton L, Reichman BS, Crown JPA, Yao TJ, et al (1994) Taxol (paclitaxel) plus recombinant human granulocyte colony-stimulating factor in the treatment of metastatic breast cancer. Oncology 51: S33-S39

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Molecular Pharmacology and Therapeutics Program, Memorial Sloan-Kettering Cancer Center and Cornell University Graduate School of Medical Sciences, 1275 York Avenue, 10021, New York, NY, USA

    Ting-Chao Chou, Glenys M. Otter & Francis M. Sirotnak

Authors
  1. Ting-Chao Chou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Glenys M. Otter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francis M. Sirotnak
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This work was supported in part by NCI grant CA18856 and by the Elsa U. Pardee Foundation

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chou, TC., Otter, G.M. & Sirotnak, F.M. Schedule-dependent synergism of taxol or taxotere with edatrexate against human breast cancer cells in vitro. Cancer Chemother. Pharmacol. 37, 222–228 (1995). https://doi.org/10.1007/BF00688320

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00688320

Key words

Search

Navigation