CHEMOTHERAPY-INDUCED MODULATION OF NATURAL-KILLER AND LYMPHOKINE-ACTIVATED KILLER-CELL ACTIVITY IN EUTHYMIC AND ATHYMIC MICE

Combinations of chemotherapy and interleukin-2 (IL-2) aimed at improvi ng therapeutic efficacy in cancer patients have generally proved disap pointing. Although chemotherapy blocks tumor growth and sometimes boos ts immune functions, most drugs are immunosuppressive, at least transi ently. Therefore, it is reasonable to assume that maximal exploitation of the immunostimulatory and antitumor activity of both modalities re quires careful coordination of chemotherapy and IL-2 timing. We analyz ed the temporal effect of 5-fluorouracil (5-FU, 100 - 120 mg/kg), cycl ophosphamide (CY, 100 mg/kg), Adriamycin (8 mg/kg) and dacarbazine (10 0 mg/kg) on the activation of natural killer/lymphokine-activated kill er (NK/LAK) cells by IL-2 in several strains of euthymic mice and in a thymic nude mice. Following in vivo or in vitro exposure to IL-2 1- 15 days after chemotherapy, the total lytic activity of the spleen and t he number of LAK precursors (LAK-p) were measured. In euthymic mice in jected with IL-2 (5 x 10(4) Cetus units twice daily for 4 - 5 days), 5 -FU augmented (up to 37-fold, days 1 - 9) and CY reduced (up to day 6) LAK activity, as compared with that in the IL-2 control. In bulk cult ures containing IL-2 (1000 CU/ml, 3 - 4 days), both 5-FU and CY reduce d LAK activity of euthymic mice splenocytes for up to 6 days after che motherapy, which was followed on day 9 by full recovery. In splenocyte s of nude mice' 5-FU increased and CY diminished LAK activation in bul k cultures, starting 3 days after chemotherapy. In athymic mice, 5-FU markedly augmented the total number of LAK-p/spleen (up to 30-fold, da ys 3 - 9), as determined by limiting-dilution cultures with IL-2 (for 7 - 8 days). In euthymic mice, in contrast, LAK-p levels decreased for up to 6 - 9 days after treatment with 5-FU, Adriamycin or dacarbazine , later recovering to pretreatment levels, whereas CY markedly increas ed LAK-p (up to 15-fold) when administered 6- 12 days before limiting- dilution culture initiation. The effect of chemotherapy on LAK and NK activity was essentially.similar. In other experiments, a subset of as ialoGM1- LAK-p was found in the spleens of 5-FU-treated mice, but not in untreated mice. Our results suggest that the immunomodulatory effec t of chemotherapy on NK/LAK activity in mice is variable and largely d epends on the drug itself, the interval between chemotherapy and IL-2 administration, the strain of mice and the assay used.