Journal of Cancer Research and Clinical Oncology

, Volume 121, Issue 12, pp 715–720 | Cite as

In vitro investigation of a combination of two drugs, cisplatin and carboplatin, as a function of the area under thec/t curve

  • Kunihiko Kobayashi
  • Shoji Kudoh
  • Toshihiko Takemoto
  • Mitsunori Hino
  • Kenji Hayashihara
  • Kazuyoshi Nakahiro
  • Masahiro Ando
  • Hisanobu Niitani
Original Paper Experimental Oncology

Abstract

The log/log relationship between the IC50 of cisplatin or carboplatin and the exposure time, determined by human tumor clonogenic assay (HTCA) and MTTAI (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay with additional incubation) using PC-14 cells, exhibited a straight line with a slope of −1, indicating that both drugs have AUC-dependent cytotoxicity (AUC, area under thec/t curve). The combined effect of cisplatin and carboplatin was estimated by the median-effect analysis using HTCA, and it was additive when the AUC ratio (AUC of free platinum from carboplatin/that from cisplatin) was low (3.2, 6.5 or 13.1 in each of PC-7, PC-9, PC-14, H-69, and K562). However, it was significantly worse at a higher AUC ratio (19.5 in PC-7, PC-9, and PC-14). The log/log relationship of each drug, determined by MTTAI using human bone marrow cells, showed that each drug exerts an AUC-dependent cytotoxicity on marrow granulocytes. When cisplatin and carboplatin were combined at an AUC ratio of 14, the therapeutic index was significantly better than that of carboplatin alone and less than that of cisplatin alone using K562, PC-9 and PC-14, indicating the usefulness of this combined therapy for tumor cells with high sensitivity to platinum compounds at this AUC ratio.

Key words

Cisplatin Carboplatin Combination effect Therapeutic index 

Abbreviations

HTCA

human tumor clonogenic assay

AUC

area under the concentration/time curve

FCS

fetal calf serum

TI

therapeutic index

CI

combination index

MTT

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

MTTAI

MTT assay with additional incubation

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References

  1. Chou TC, Talalay P (1985) Dose-effect analysis with microcomputers. Elsevier, UK, p1Google Scholar
  2. Evans BD, Raju KS, Calvert AH, Harland SJ, Wiltshaw E (1983) Phase study of JM-8, a new platinum analog, in advanced ovarian carcinoma. Cancer Treat Rep 67:997–1000PubMedGoogle Scholar
  3. Gandara DR, Wold H, Peres EA, Deisseroth AB, Meyers DF, Hanningan KM, Gregorio WD (1989) Cisplatin dose intensity in non-small cell lung cancer: phase II results of a day 1 and day 8 high-dosc regimen. J Natl Cancer Inst 81:790–794PubMedGoogle Scholar
  4. Ginsberg RJ, Kris MG, Armstrong JG (1993) Cancer of the lung. In: DeVita VT Jr, Hellman S, Rosenberg SA (eds) Cancer: principle and practice of oncology, 4th edn. Lippincott, Philadelphia, pp 673–723Google Scholar
  5. Gralla RJ, Casperc ES, Kelsen DP, Braun DW, Dukeman ME, Martini N, Young CW, Golbey RB (1981) Cisplatin and vindesine combination chemotherapy for advanced carcinoma of the lung: a randomized trial investigating two dosage schedules. Ann Intern Med 95:412–420Google Scholar
  6. Hamburger AM, Salmon SE (1977) Primary bioassay of human tumor stem cells. Science 197:461PubMedGoogle Scholar
  7. Hayata Y, Tsuji K (1975) Lung cancer (in Japanese). In: Ohboshi S, Sugano H (eds) Culture of human cancer cells. Asakurashoten, Tokyo, p 131Google Scholar
  8. Knox RJ, Friedros F, Lydall DA, Roberts JJ (1986) Mechanism of cytotoxicity of anticancer platinum drugs: evidence thatcis-diammine-dichloroplatinum(II) andcis-diammine(1,1-cyclobutanedicarboxylato)platinum (II) differ only in the kinetics of their interaction with DNA. Cancer Res 46:1972–1979PubMedGoogle Scholar
  9. Kobayashi K, Takemoto T, Hino M, Hayashihara K, Nakahiro K, Wasai S, Niitani H (1992) Estimating doses of anti-cancer agents in sensitivity tests in vitro (in Japanese). Jpn J Cancer Chemother 19:399–403Google Scholar
  10. Koeller JM, Trump DL, Tutsch KD, Earhart RH, Davis TE, Tormey DC (1986) Phase I clinical trial and pharmacokinetics of Carboplatin (NSC241240) by single monthly 30-minute infusion, Cancer 57:222–225PubMedGoogle Scholar
  11. Kreisman H, Goutsou M, Mondea SC, Graziano SL, Costanza ME, Green MR (1990) Cisplatin-carboplatin therapy in extensive non-small cell lung cancer: a Cancer and Leukemia Group B study. Eur J Cancer 26:1057–1060PubMedGoogle Scholar
  12. Kris MG, Gralla RJ, Wertheim MS, Kelsen DP, O'Connell JP, Burke MT, Fiore JJ, Cibas IR, Heelan RT (1986) Trial of the combination of mitomycin, vindesine and cisplatin in patients with advanced non-small cell lung cancer. Cancer Treat Rep 70:1091–1096.PubMedGoogle Scholar
  13. Ozawa S, Sugiyama Y, Mitsuhashi Y, Kobayashi T, Inaba M (1988) Cell killing action of cycle phase-non-specific antitumor agents is dependent on concentration-time product. Cancer Chemother Pharmacol 21:185–190PubMedGoogle Scholar
  14. Piccart MJ, Nogaret JM, Marcelis L, Ries HL, Kains JP, Gobert P, Domange AM, Sculier JP, Gompel C (1990) Cisplatin combined with carboplatin: a new way of intensification of platinum dose in the treatment of advanced ovarian cancer. J Natl Cancer Inst 82:703–707PubMedGoogle Scholar
  15. Ruckdeschel JC, Finkelstein DM, Ettinger DS, Creech RH, Mason BA, Joss RA, Vogl S (1986) A randomized trial of the four most active regimens for metastatic non-small cell lung cancer. J Clin Oncol 4:14–22PubMedGoogle Scholar
  16. Sasaki Y, Tamura T, Eguchi K, Shinkai T, Fujiwara Y, Fukuda M, Ohe Y, Bungo M, Horiuchi N, Niimi S, Minato K, Nakagawa K, Saijo N (1989) Pharmacokinetics of (glycolato-O,O′)-diammine platinum II, a new platinum derivative, in comparison with cisplatin and carboplatin. Cancer Chemother Pharmacol 23:243PubMedGoogle Scholar
  17. Takahashi H, Sakai Y, Saijo N, Sakurai M, Nakano H, Nagasawa K, Hoshi A, Jett RJ, Hong WA (1987) In vitro colony inhibition of carboplatin against stomach and lung cancer cell lines in comparison with cisplatin. Cancer Chemother Pharmacol 19:197–200PubMedGoogle Scholar
  18. Takemoto T (1993) A comparative study of chemosensitivity tests in vitro for AUC-dependent drugs focusing on the usefulness of MTT assay with drug washout and additional incubation (M-MTT) (in Japanese). J Nippon Med Sch 60:140–155Google Scholar
  19. Yoshimura A, Gemma A, Yoshimori K, Shibuya M, Niitani H, Yamada K, Ando M, Takenaka K, Hasegawa H, Tsuboi E (1992) A phase I trial of combination of cisplatin and carboplatin in advanced non-small cell lung cancer. An intensification of two platinum compounds (in Japanese). J Jpn Lung Cancer Soc 32:827–835Google Scholar
  20. Yoshimura A, Yamano Y, Gemma A, Yoshimori K, Hayashihara K, Taniguchi Y, Uematsu K, Shibuya M, Kudoh S, Niitani H, Hasegawa K, Tsuboi E (1993) An early phase II trial combining cisplatin and carboplatin in advanced non-small cell lung cancer (in Japanese). Jpn J Cancer Chemother 20:503–508Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • Kunihiko Kobayashi
    • 1
    • 2
  • Shoji Kudoh
    • 1
  • Toshihiko Takemoto
    • 1
  • Mitsunori Hino
    • 1
  • Kenji Hayashihara
    • 1
  • Kazuyoshi Nakahiro
    • 1
  • Masahiro Ando
    • 1
  • Hisanobu Niitani
    • 1
  1. 1.Fourth Department of Internal MedicineNippon Medical SchoolTokyoJapan
  2. 2.Department of PulmonologyInternational Medical Center of JapanTokyoJapan

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