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Schedule-dependent synergism and antagonism between pemetrexed and paclitaxel in human carcinoma cell lines in vitro

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Abstract

Pemetrexed is a novel multitargeted antifolate with significant clinical activity against a variety of tumors. We studied the schedule-dependent cytotoxic effects of pemetrexed in combination with paclitaxel in vitro to improve our understanding of how this combination might be used clinically. Human lung cancer A549 cells, breast cancer MCF7, ovarian cancer PA1, and colon cancer WiDr cells were exposed to both pemetrexed and paclitaxel in vitro. Cell growth inhibition after 5 days was determined and the effects of drug combinations were analyzed by the isobologram method (Steel and Peckham). Simultaneous exposure to pemetrexed and paclitaxel for 24 h produced antagonistic effects in A549 and PA1 cells, additive/antagonistic effects in MCF7 cells, and additive effects in WiDr cells. Pemetrexed for 24 h followed by paclitaxel for 24 h produced synergistic effects in A549 and MCF7 cells and additive effects in PA1 and WiDr cells, while the reverse sequence produced additive effects in all four cell lines. Cell cycle analysis supported these observations. Our findings suggest that the simultaneous administration of pemetrexed and paclitaxel is suboptimal. The optimal schedule of pemetrexed in combination with paclitaxel is the sequential administration of pemetrexed followed by paclitaxel, and this schedule should be assessed in clinical trials for the treatment of solid tumors.

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References

  1. Arbuck SG (1995) Paclitaxel: current developmental approaches of the National Cancer Institute. Semin Oncol 22:55–56

    CAS  Google Scholar 

  2. Britten CD, Izbicka E, Hilsenbeck S, Lawrence R, Davidson K, Cerna C, Gomez L, Rowinsky EK, Weitman S, Van Hoff DD (1999) Activity of the multitargeted antifolate MTA in the human tumor cloning assay. Cancer Chemother Pharmacol 44:105–110

    Article  CAS  PubMed  Google Scholar 

  3. Calvert AH, Walling JM (1998) Clinical studies with MTA. Br J Cancer 78 [Suppl 3]:35–40

    CAS  PubMed  Google Scholar 

  4. Celio L, Buzzoni R, Longarini R, Marchiano A, Bajetta E (2002) Pemetrexed in gastric cancer: clinical experience and future perspectives. Semin Oncol 29 [Suppl 18]:63–68

    Article  Google Scholar 

  5. Chen VJ, Bewley JR, Smith PG, Andis SL, Schultz RM, Iversen PW, Tonkinson JL, Shih C (2000) An assessment of the antithymine and antipurine characteristics of MTA (LY231514) in CCRF-CEM cells. Adv Enzyme Regul 40:143–154

    Article  CAS  PubMed  Google Scholar 

  6. Donehower RC, Rowinsky EK (1993) An overview of experience with taxol (paclitaxel) in the USA. Cancer Treat Rev 19 [Suppl C]:63–78

    Article  PubMed  Google Scholar 

  7. Habeck LL, Mendelsohn LG, Shih C, Taylor EC, Colman PD, Gossett LS, Leitner TA, Schultz RM, Andis SL, Moran RG (1995) Substrate specificity of mammalian folypolyglutamate synthetase for 5,10-dideazatetrahydrofolate analogs. Mol Pharmacol 48:326–333

    CAS  PubMed  Google Scholar 

  8. Haller DG (2002) Future directions in the treatment of pancreatic cancer. Semin Oncol 29 [Suppl 20]:31–39

    Article  CAS  Google Scholar 

  9. Hanauske AR, Chen V, Paoletti P, Niyikiza C (2001) Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors. Oncologist 6:363–373

    CAS  PubMed  Google Scholar 

  10. Hochster H (2002) The role of pemetrexed in the treatment of colorectal cancer. Semin Oncol 29 [6 Suppl 18]:54–56

    Article  Google Scholar 

  11. Kano Y, Ohnuma T, Okano T, Holland JF (1988) Effects of vincristine in combination with methotrexate and other antitumor agents in human acute lymphoblastic leukemia cells in culture. Cancer Res 48:351–356

    CAS  PubMed  Google Scholar 

  12. Kano Y, Sakamoto S, Kasahara T, Akutsu M, Inoue Y, Miura Y (1991) In vitro effects of amsacrine in combination with other anticancer agents. Leuk Res 15:1059–1064

    Article  CAS  PubMed  Google Scholar 

  13. Kano Y, Akutsu M, Tsunoda S, Ando J, Matsui J, Suzuki K, Ikeda T, Inoue Y, Adachi K (1996) Schedule-dependent interaction between paclitaxel and 5-fluorouracil in human carcinoma cell lines in vitro. Br J Cancer 74:704–710

    CAS  PubMed  Google Scholar 

  14. Kano Y, Akutsu M, Tsunoda S, Suzuki K, Adachi K (1998) In vitro schedule-dependent interaction between paclitaxel and SN-38 (the active metabolite of irinotecan) in human carcinoma cell lines. Cancer Chemother Pharmacol 42:91–98

    Article  CAS  PubMed  Google Scholar 

  15. Kano Y, Akutsu M, Tsunoda S, Furuta M, Yazawa Y, Ando J (1998) Schedule-dependent synergism and antagonism between paclitaxel and methotrexate in human carcinoma cell lines. Oncol Res 10:347–354

    CAS  PubMed  Google Scholar 

  16. Kano Y, Akutsu M, Tsunoda S, Mano H, Sato Y, Honma Y, Furukawa Y (2001) In vitro cytotoxic effects of a tyrosine kinase inhibitor STI571 in combination with commonly used antileukemic agents. Blood 97:1999–2007

    Article  CAS  PubMed  Google Scholar 

  17. Lieu CH, Chang YN, Lai YK (1997) Dual cytotoxic mechanisms of submicromolar taxol on human leukemia HL-60 cells. Biochem Pharmacol 53:1587–1596

    Article  CAS  PubMed  Google Scholar 

  18. McDonald AC, Vasey PA, Adams L, Walling J, Woodworth JR, Abrahams T, McCarthy S, Bailey NP, Siddiqui N, Lind MJ, Calvert AH, Twelves CJ, Cassidy J, Kaye SB (1998) A phase I and pharmacokinetic study of LY231514, the multitargeted antifolate. Clin Cancer Res 4:605–610

    CAS  PubMed  Google Scholar 

  19. O’Shaughnessy JA, Gennari A, Conte P (2002) Pemetrexed: a promising new treatment for breast cancer. Semin Oncol 29 [2 Suppl 5]:36–41

    Article  CAS  Google Scholar 

  20. Paz-Ares L, Ciruelos E, Garcia-Carbonero R, Castellano D, Lopez-Martin A, Cortes-Funes H (2002) Pemetrexed in bladder, head and neck, and cervical cancers. Semin Oncol 29 [Suppl 18]:69–75

    Article  Google Scholar 

  21. Paz-Ares L, Bezares S, Tabernero JM, Castellanos D, Cortes-Funes H (2003) Review of a promising new agent—pemetrexed disodium. Cancer [Suppl] 97:2056–2063

    Article  CAS  PubMed  Google Scholar 

  22. Raymond E, Louvet C, Tournigand C, Coudray AM, Faivre S, De Gramont A, Gespach C (2002) Pemetrexed disodium combined with oxaliplatin, SN38, or 5-fluorouracil, based on the quantitation of drug interactions in human HT29 colon cancer cells. Int J Oncol 21:361–367

    CAS  PubMed  Google Scholar 

  23. Rinaldi DA (1999) Overview of phase I trials of multitargeted antifolate (MTA, LY231514). Semin Oncol 26 [Suppl 6]:82–88

    CAS  Google Scholar 

  24. Rinaldi DA, Burris HA, Dorr FA, Woodworth JR, Kuhn JG, Eckardt JR, Rodriguez G, Corso SW, Fields SM, Langley C, Clark G, Faries D, Lu P, Van Hoff DD (1995) Initial phase I evaluation of the novel thymidylate synthase inhibitor, LY231514, using the modified continual reassessment method for dose escalation. J Clin Oncol 13:2842–2850

    CAS  PubMed  Google Scholar 

  25. Rinaldi DA, Kuhn JG, Burris HA, Dorr FA, Rodriguez G, Eckhardt SG, Jones S, Woodworth JR, Baker S (1999) A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation. Cancer Chemother Pharmacol 44:372–380

    Article  CAS  PubMed  Google Scholar 

  26. Scagliotti GV, Shin DM, Kindler HL, Vasconcelles MJ, Keppler U, Manegold C, Burris H, Gatzemeier U, Blatter J, Symanowski JT, Rusthoven JJ (2003) Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma. J Clin Oncol 21:1556–1561

    Article  PubMed  Google Scholar 

  27. Schiff PB, Fant J, Horwitz SB (1979) Promotion of microtubule assembly in vitro by taxol. Nature 277:665–667

    CAS  PubMed  Google Scholar 

  28. Schultz RM, Dempsey JA, Kraus LA, Schmid SM, Calvete JA, Laws AL (1999) In vitro sequence dependence for the multitargeted antifolate (MTA, LY231514) combined with other anticancer agents. Eur J Cancer 35 [Suppl 4]:S194

    Article  Google Scholar 

  29. Shih C, Thornton DE (1998) Preclinical pharmacology studies and the clinical development of a novel multitargeted antifolate, MTA (LY231514). In: Jackman AL (ed) Anticancer drug development guide: antifolate drugs in cancer therapy. Humana, Totowa, p 183

  30. Shih C, Chen VJ, Gossett LS, Gates SB, MacKellar WC, Habeck LL, Shackelford KA, Mendelsohn LG, Soose DJ, Patel VF, Andis SL, Bewley JR, Rayl EA, Moroson BA, Beardsley GP, Kohler W, Ratnam M, Schultz RM (1997) LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res 57:1116–1123

    CAS  PubMed  Google Scholar 

  31. Shih C, Habeck LL, Mendelsohn LG, Chen VJ, Schultz RM (1998) Multiple folate enzyme inhibition: mechanism of a novel pyrrolopyrimidine-based antifolate LY231514 (MTA). Adv Enzyme Regul 38:135–152

    Article  CAS  PubMed  Google Scholar 

  32. Steel GG, Peckham MJ (1979) Exploitable mechanisms in combined radiotherapy–chemotherapy: the concept of additivity. Int J Radiat Oncol Biol Phys 5:85–91

    CAS  PubMed  Google Scholar 

  33. Taylor EC, Kuhnt D, Shih C, Rinzel SM, Grindey GB, Barredo J, Jannatipour M, Moran RG (1992) A dideazatetrahydrofolate analogue lacking a chiral center at C-6, N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid, is an inhibitor of thymidylate synthase. J Med Chem 35:4450–4454

    CAS  PubMed  Google Scholar 

  34. Teicher BA, Alvarez E, Liu P, Lu K, Menon K, Dempsey J, Schultz RM (1999) MTA (LY231514) in combination treatment regimens using human tumor xenografts and the EMT-6 murine mammary carcinoma. Semin Oncol 28:55–62

    Google Scholar 

  35. Teicher BA, Chen V, Shih C, Menon K, Forler PA, Phares VG, Amsrud T (2000) Treatment regimens including the multitargeted antifolate LY231514 in human tumor xenografts. Clin Cancer Res 6:1016–1023

    CAS  PubMed  Google Scholar 

  36. Tesei A, Ricotti L, De Paola F, Amadori D, Frassineti GL, Zoli W (2002) In vitro schedule-dependent interactions between the multitargeted antifolate LY231514 and gemcitabine in human colon adenocarcinoma cell lines. Clin Cancer Res 8:233–239

    CAS  PubMed  Google Scholar 

  37. Tomek S, Emri S, Krejcy K, Manegold C (2003) Chemotherapy for malignant pleural mesothelioma: past results and recent developments. Br J Cancer 88:167–174

    Article  CAS  PubMed  Google Scholar 

  38. Tonkinson JL, Marder P, Andis SL, Schultz RM, Gossett LS, Shih C, Mendelsohn LG (1997) Cell cycle effects of antifolate antimetabolites: implications for cytotoxicity and cytostasis. Cancer Chemother Pharmacol 39:521–531

    Article  CAS  PubMed  Google Scholar 

  39. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P (2003) Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21:2636–2644

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by a Grant-in-Aid for Cancer Research (11-8) from the Ministry of Health and Welfare and by a Grant-in-Aid for Research on the Second-Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health and Welfare of Japan.

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Authors and Affiliations

  1. Division of Hematology, Tochigi Cancer Center, Yonan, Utsunomiya, Tochigi, 320-0834, Japan

    Yasuhiko Kano, Miyuki Akutsu, Saburo Tsunoda & Tohru Izumi

  2. Division of Medical Oncology, Tochigi Cancer Center, Utsunomiya, Tochigi, Japan

    Kiyoshi Mori & Hirofumi Fujii

  3. Division of Orthopedic Oncology, Tochigi Cancer Center, Utsunomiya, Tochigi, Japan

    Yasuo Yazawa

  4. Center for Molecular Medicine, Department of Hematology, Jichi Medical School, Minamikawachi, Tochigi, Japan

    Hiroyuki Mano & Yusuke Furukawa

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  1. Yasuhiko Kano
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  2. Miyuki Akutsu
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  9. Yusuke Furukawa
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Correspondence to Yasuhiko Kano.

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Kano, Y., Akutsu, M., Tsunoda, S. et al. Schedule-dependent synergism and antagonism between pemetrexed and paclitaxel in human carcinoma cell lines in vitro. Cancer Chemother Pharmacol 54, 505–513 (2004). https://doi.org/10.1007/s00280-004-0839-5

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  • DOI: https://doi.org/10.1007/s00280-004-0839-5

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