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Potentiation by Interleukin 1 of Cisplatin and Carboplatin Antitumor Activity: Schedule-dependent and Pharmacokinetic Effects in the RIF-1 Tumor Model¹

Departments of Otolaryngology [M-J. C., W-D. Y., R. A. M., C. S. J.] and Pharmacology [C. S. J.], University of Pittsburgh School of Medicine, Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213; University of Maryland Cancer Center, Division of Hematology-Oncology, Department of Medicine [L. M. R., M. J. E., K. E.], University of Maryland School of Medicine, Baltimore, Maryland 21201; Brigham and Women's Hospital [D. R. V.], Boston, Massachusetts 02115; and Department of Biology [P. F.], New York University, New York, New York 10003

We have previously demonstrated that the cytokine interleukin 1 (IL-1) significantly potentiates the antitumor activity of a variety of chemotherapeutic agents, including cisplatin (cDDP). In studies described here, we examined the potential of combining IL-1 and the platinum analogue carboplatin (CBDCA) and compared the schedule-dependent and pharmacokinetic effects for IL-1 combinations with cDDP and CBDCA. RIF-1 tumor-bearing mice (C3H/HeJ) received i.p. injections of varying doses of CBDCA, alone or concurrently with IL-1 (48 or 480 µg/kg). Clonogenic cell kill and tumor regrowth delay were significantly increased when CBDCA was combined with IL-1, at both doses, compared to either CBDCA or IL-1 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 alone, IL-1 receptor antagonist only partially blocked IL-1 enhancement of CBDCA or cDDP-mediated tumor cell kill. The IL-1 enhancement of CBDCA-mediated tumor cell kill was highly schedule dependent, with maximum antitumor activity observed when IL-1 was administered 4–12 h before CBDCA. In contrast, administration of IL-1 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. Tumor and normal tissue platinum content were significantly increased by IL-1 in animals treated with CBDCA (P < 0.01) but not in those treated with cDDP. The observed differences between cDDP and CBDCA may be explained by their known differential rates of clearance and protein binding affinities and are compatible with an induced alteration in CBDCA pharmacokinetics.

¹ This work was supported by Public Health Service Grants CA48077 and CA56756 from the National Cancer Institute, NIH, Department of Health and Human Services; the Mary Hillman Jennings Foundation; and the John R. McCune Charitable Trust Foundation. L. M. R. is the recipient of a Gordon Richards Fellowship of the Canadian Cancer Society, Ontario Division, and a McEachern Fellowship of the Canadian Cancer Society, National Division.

² Present address: Hamilton Regional Cancer Center, Hamilton, Ontario, Canada L8V 5C2.

³ To whom requests for reprints should be addressed, at the University of Pittsburgh School of Medicine, Department of Otolaryngology, 203 Lothrop Street, Room 110, Pittsburgh, PA 15213.

Received 4/ 5/94. Accepted 8/17/94.

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