Chang M J, Yu W D, Reyno L M, Modzelewski R A, Egorin M J, Erkmen K, Vlock D R, Furmanski P, Johnson C S
Department of Otolaryngology, University of Pittsburgh School of Medicine, Pennsylvania 15213.
Cancer Res. 1994 Oct 15;54(20):5380-6.
We have previously demonstrated that the cytokine interleukin 1 alpha (IL-1 alpha) 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 alpha and 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. injections of varying doses of CBDCA, alone or concurrently with IL-1 alpha (48 or 480 micrograms/kg). Clonogenic cell kill and tumor regrowth delay were significantly increased when CBDCA was combined with IL-1 alpha, at 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 alpha enhancement of CBDCA or cDDP-mediated tumor cell kill. The IL-1 alpha enhancement of CBDCA-mediated tumor cell kill was highly schedule dependent, with maximum antitumor activity observed when IL-1 alpha was 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 increased by IL-1 alpha 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.
我们之前已经证明，细胞因子白细胞介素1α（IL-1α）能显著增强包括顺铂（cDDP）在内的多种化疗药物的抗肿瘤活性。在本文所述的研究中，我们研究了联合使用IL-1α与铂类类似物卡铂（CBDCA）的可能性，并比较了IL-1α与cDDP和CBDCA联合使用时的时间依赖性和药代动力学效应。携带RIF-1肿瘤的小鼠（C3H/HeJ）腹腔注射不同剂量的CBDCA，单独注射或与IL-1α（48或480微克/千克）同时注射。与单独使用CBDCA或IL-1α相比，当CBDCA与IL-1α联合使用时，两种剂量下的克隆源性细胞杀伤和肿瘤生长延迟均显著增加（分别为P < 0.001和P < 0.01）。虽然用IL-1受体拮抗剂预处理可阻断IL-1α单独诱导的急性肿瘤出血反应，但IL-1受体拮抗剂仅部分阻断IL-1α增强CBDCA或cDDP介导的肿瘤细胞杀伤作用。IL-1α增强CBDCA介导的肿瘤细胞杀伤作用高度依赖时间，当在CBDCA给药前4 - 12小时给予IL-1α时观察到最大抗肿瘤活性。相比之下，在cDDP给药前24小时或给药后6小时给予IL-1α，其抗肿瘤活性与同时给予cDDP和IL-1α相同。在用CBDCA治疗的动物中，IL-1α显著增加了肿瘤和正常组织中的铂含量（P < 0.01），但在用cDDP治疗的动物中未观察到这种情况。观察到的cDDP和CBDCA之间的差异可能由它们已知的不同清除率和蛋白质结合亲和力来解释，并且与CBDCA药代动力学的诱导改变相一致。
