Effects of CPT‐11 in combination with other anti‐cancer agents in culture

Abstract

CPT‐11, 7‐ethyl‐10‐[4‐( 1 ‐piperidino)‐1 ‐piperidino]carbonyloxy camptothecin, is a newly developed water‐soluble camptothecin derivative now undergoing phase‐II evaluation. In an attempt to establish whether the combination of CPT‐11 with other standard anti‐cancer agents would be of any benefit, we studied the effects of CPT‐11 in combination with 11 other anti‐cancer agents on a human T‐cell leukemia cell line, MOLT‐3, in culture. We used both CPT‐11 and SN‐38 (active substance of CPT‐11 in vivo), for our study. Cells were incubated for 3 days in the presence of 2 drugs (CPT‐11 or SN‐38 and another drug) and cytotoxic effects were determined by MTT assay. The effects of drug combinations on ID₅₀ were analyzed, by an improved isobologram method. Supra‐additive and marginal supra‐additive effects (synergism) were observed for CPT‐11 in combination with cisplatin, cytosine arabinoside and mitomycin C. Additive effects were observed for its combination with amsacrine, bleomycin, doxorubicin, etoposide, 5‐fluorouracil, mitoxantrone and vincristine. Alternate sub‐additive and protective effects (antagonism) were observed for CPT‐11 in combination with methotrexate. Similar tendencies were observed for SN‐38 in combination with other agents. These results suggest that CPT‐11 in simultaneous administration with a majority of anti‐cancer agents has an advantage for cytokilling. Of these agents, cisplatin, cytosine arabinoside and mitomycin C are most suitable for simultaneous administration with CPT‐11.