Doxorubicin sensitivity pattern in a panel of small-cell lung-cancer cell lines: correlation to etoposide and vincristine sensitivity and inverse correlation to carmustine sensitivity.

The aim of our investigations is to evaluate whether the sensitivity patterns of small-cell lung-cancer (SCLC) cell lines in vitro can be used in evaluating new drugs and in selecting drugs for the optimization of combination therapy. In our attempts to obtain a panel of cell lines demonstrating differential patterns in sensitivity, we have developed three SCLC lines exhibiting different types of multidrug resistance (MDR). In the present investigations we compared the sensitivity patterns shown by five wild-type SCLC lines and three MDR lines in response to six different types of drugs: doxorubicin, cytarabine, carmustine, cisplatin, vincristine, and etoposide. In the wild-type SCLC cell lines, the range of variation in sensitivity to all drugs was within a factor of 10. Cell lines showing low sensitivity to doxorubicin also exhibited low sensitivity to etoposide and vincristine, and vice versa. In contrast, the pattern of sensitivity to carmustine was almost the opposite of that to doxorubicin. A tendency to an inverse relationship between doxorubicin and carmustine sensitivity was also observed when doxorubicin sensitivity was reduced in near stationary cells and in cells exposed to the metabolic inhibitor 2-deoxy-D-glucose. In agreement with the pattern observed for the wild-type lines, all of the MDR sublines demonstrated collateral sensitivity to carmustine. As to cytarabine, the wild-type lines expressed a sensitivity pattern similar to that shown in response to doxorubicin. Interestingly, the opposite pattern was found in the MDR lines, as all three demonstrated cytarabine hypersensitivity. The combination of alkylating agents and "MDR" drugs are of proven clinical benefit in the treatment of solid tumors, as is the combination of anthracycline and cytarabine in acute myeloid leukemia. The experimentally derived sensitivity data on cytarabine, alkylating agents, and MDR drugs (i.e., etoposide, doxorubicin, vincristine) thus resemble the clinical experience with these drugs, and we conclude that the use of a clonogenic assay on the described panel of SCLC cell lines can give valuable information for the selection of agents for combination therapy.