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Synergistic interaction between cisplatin and gemcitabine in vitro
A M Bergman1, V W Ruiz van Haperen, G Veerman
1Department of Oncology, Free University Hos-pital, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
Summary
This study investigated the synergistic effects of gemcitabine (dFdC) and cisplatin (CDDP) on cancer cell growth. The combination showed synergistic effects in ovarian cancer cells, particularly with specific preincubation strategies, suggesting potential for enhanced chemotherapy.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Gemcitabine (2',2'-Difluorodeoxycytidine, dFdC) and cisplatin (cis-diamminedichloroplatinum, CDDP) are antineoplastic agents used against various carcinomas.
- Their distinct mechanisms of action suggest potential for complementary effects in cancer treatment.
Purpose of the Study:
- To investigate the synergistic interaction between dFdC and CDDP on the growth inhibition of human ovarian carcinoma, head and neck squamous cell carcinoma, and murine colon carcinoma cell lines.
- To evaluate the impact of different drug exposure sequences and durations on synergistic effects.
Main Methods:
- Utilized human ovarian carcinoma (A2780, ADDP, AG6000), head and neck squamous cell carcinoma (UMSCC-22B), and murine colon carcinoma (C26-10) cell lines.
- Exposed cells to dFdC and CDDP as single agents and in combination (1:500 molar ratio) for varying durations (1-72 hours).
- Assessed synergy using multiple drug effect analysis and investigated mechanisms including dFdCTP accumulation and DNA strand breaks.
Main Results:
- Simultaneous dFdC and CDDP exposure demonstrated synergism in A2780 and ADDP cells at 24 and 72 hours, but antagonism at shorter intervals.
- No synergism was observed with prolonged simultaneous exposure in UMSCC-22B and C26-10 cells.
- A 4-hour preincubation with CDDP followed by dFdC, or a 4-hour dFdC preincubation followed by combination therapy, yielded synergistic effects across most cell lines.
- CDDP did not enhance dFdCTP accumulation and tended to decrease DNA double-strand breaks in combination therapy.
Conclusions:
- The combination of dFdC and CDDP can exhibit synergistic anti-cancer effects, with the efficacy dependent on the sequence and duration of drug administration.
- Preincubation strategies, particularly with CDDP followed by dFdC, enhance synergistic activity in various cancer cell lines.
- The synergistic mechanism may involve dFdC incorporation into DNA and/or CDDP-DNA adduct formation, rather than increased dFdCTP levels or DNA strand breaks.