Effect of cisplatin on interleukin-2-induced lymphokine-activated killer cell generation and cytotoxicity against malignant melanoma cells

Biological treatment approaches using interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells have been evaluated clinically in patients with malignant melanoma and have met with only modest success. More recently, clinical trials combining biological agents and cytotoxic drugs have been initiated. Such clinical trials should be based on appropriate preclinical studies to determine the potential for synergy as well as antagonism between the two modalities. In this in vitro investigation, pre-incubation of fresh human peripheral blood mononuclear cells with high concentrations of the cytotoxic agent cisplatin (100 μg/ml) for 1 h, resulted in an inhibition of the cytotoxic activity against tumor cells normally induced by IL-2 (i.e. LAK cell induction was inhibited). The inhibitory effects of high concentrations of cisplatin did not resolve after up to 24 h of washout post-incubation with cisplatin. In addition, incubation with high concentrations of cisplatin reduced the cytotoxic activity of fully generated LAK cells. However, lower concentrations of cisplatin (2-10 μg/ml) had minimal effects of LAK cell induction or activity. When tested against an early-passage melanoma cell line, the combination of cisplatin and LAK cells gave additive cytotoxicity, which was not altered by the sequence of administration of the two agents. These results may have relevance to the design of clinical trials of cisplatin and IL-2 in settings where regional exposure to high concentrations of cytotoxic drugs is attempted (e.g. isolated limb perfusion in malignant melanoma and intraperitoneal therapy for ovarian cancer).