Synergistic interactions of combinations of topotecan with standard drugs in primary cultures of human tumor cells from patients

Abstract

Objective: Combination therapies are important in the treatment of many tumor types. This study was undertaken to find candidates for combination therapy with the novel topoisomerase I inhibitor topotecan.

Methods: The cytotoxic effect of topotecan alone and in combination with five standard cytotoxic drugs was studied in 27 primary cultures of human tumor cells from patients with various diagnoses using the fluorometric microculture cytotoxicity assay (FMCA). The combinations were analysed according to the multiplicative concept of drug interaction.

Results: The additive model was shown to be a better descriptor than the effect of the most effective agent (D_max) for all drug combinations tested. Topotecan in combination with cisplatin (CisP) was the drug combination showing synergy in the highest percentage of samples (54%), followed by topotecan in combination with doxorubicin (Dox; 39%), etoposide (P16; 23%), paclitaxel in the formulation Taxol (22%) and cytarabine (AraC; 12%). The high percentage of synergistic interactions was especially pronounced in solid tumors. In 28% of the samples tested, drug sensitivity testing of only single drugs failed to predict response to the drugs in combination.

Conclusion: Cisplatin and doxorubicin showed promising effects in combination with topotecan, and clinical trials with these combinations seem warranted. The results also indicate the value of testing drug combinations in in vitro drug sensitivity testing.