POTENTIATION BY INTERLEUKIN-1-ALPHA OF CISPLATIN AND CARBOPLATIN ANTITUMOR-ACTIVITY - SCHEDULE-DEPENDENT AND PHARMACOKINETIC EFFECTS IN THERIF-1 TUMOR-MODEL

We have previously demonstrated that the cytokine interleukin 1 alpha (IL-1 alpha) significantly potentiates the antitumor activity of a var iety of chemotherapeutic agents, including cisplatin (cDDP). In studie s described here, we examined the potential of combining IL-1 alpha an d the platinum analogue carboplatin (CBDCA) and compared the schedule- dependent and pharmacokinetic effects for IL-1 alpha combinations with cDDP and CBDCA. RIF-1 tumor-bearing mice (C3H/HeJ) received i.p. inje ctions of varying doses of CBDCA, alone or concurrently with IL-1 alph a (48 or 480 mu g/kg). Clonogenic cell kill and tumor regrowth delay w ere significantly increased when CBDCA was combined with IL-1 alpha, a t both doses, compared to either CBDCA or IL-1 alpha alone (P < 0.001 and P < 0.01, respectively). Although pretreatment with IL-1 receptor antagonist blocked the acute tumor hemorrhagic response induced by IL- 1 alpha alone, IL-1 receptor antagonist only partially blocked IL-1 al pha enhancement of CBDCA or cDDP-mediated tumor cell kill. The IL-1 al pha enhancement of CBDCA-mediated tumor cell kill was highly schedule dependent, with maximum antitumor activity observed when IL-1 alpha wa s administered 4-12 h before CBDCA. In contrast, administration of IL- 1 alpha from 24 h before or as late as 6 h after cDDP resulted in the same antitumor activity as simultaneous administration of cDDP and IL- 1 alpha. Tumor and normal tissue platinum content were significantly i ncreased by IL-1 alpha in animals treated with CBDCA (P < 0.01) but no t in those treated with cDDP. The observed differences between cDDP an d CBDCA may be explained by their known differential rates of clearanc e and protein binding affinities and are compatible with an induced al teration in CBDCA pharmacokinetics.