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. 1995 Dec;121(12):715–720. doi: 10.1007/BF01213317

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

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
PMCID: PMC12201400  PMID: 7499442

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

Footnotes

This work was supported by grants from the Ministry of Health and Welfare of Japan

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