We optimized the modulation of drug resistance by the irreversible augmentation of cytotoxicity of coincubating vinblastine (VNB) with VP-16 and the reversible increase in cytotoxicity of coincubation of verapamil (VPL) with VNB and VP-16. VPL was administered as a loading dose (i.v.) (0.15 mg/kg) and then administered as a constant infusion (0.005 mg/kg) over 6 days. 24 h after verapamil, VNB 2 mg/m2 IVP was administered and followed 1 h later by a 5-day simultaneous continuous infusion of VP-16 (200 mg/m2/day) to seven pediatric patients (11 courses) with refractory malignancies. The mean age at treatment was 7.5 ± 5.3 years, mean prior anthracycline dose (303 ± 210 mg/m2) with a range of 0–606 mg/m2. Toxicity was limited to cardiac and hematological. The median nadir of the WBC was 900 at 14.5 ± 0.5 days and platelet count 32,000 at 15.5 ± 0.8 days. There were two episodes of bacterial sepsis both of which responded to i.v. antibiotics. Five of 11 courses resulted in first-degree block and one course in second-degree block. At Hour 120 of the VPL infusion the PR interval was 0.18 ± 0.01 versus 0.13 ± 0.01 at Hour 0 (P < 0.0004). The ejection fraction by two-dimensional echocardiogram was not significantly different at Hour 0, 24, or 120 of the infusion (60.6 ± 2.7 versus 52.7 ± 5.1 versus 51.8 ± 5.0%). The cardiac index was also not significantly different at Hour 0, 24, or 120 (4.39 ± 0.2 versus 4.21 ± 0.6 versus 3.91 ± 0.5 liters/min/m2). The 15-min VPL level was 1954.5 ± 391/ng/ml and steady state levels at Hour 24 and 120 of the infusion were 468.1 ± 59 and 422.8 ± 52 ng/ml, respectively. Two of 11 treatment courses resulted in hypotension secondary to inordinately high 24-h levels of VPL (1233 and 1263 ng/ml). These two episodes required inotropic support but did not require the discontinuation of VPL. There were 8 of 11 partial responses, the majority of which consisted of peripheral cytoreduction of leukemic blasts and one M-2A response in AML. The levels of VPL achieved in this study have been shown to augment the in vitro cytotoxicity of vinblastine and VP-16 to resistant cell lines. Further clinical studies are needed to determine the maximal-tolerated dose of VPL in a Phase I study and to examine its efficacy in selected relapsed pediatric patients.

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This project was supported with a grant from The Pediatric Cancer Research Foundation of Orange County. This study was presented in part at the Clinical Investigative Section of the American Association of Cancer Research meetings, May, 1988, New Orleans, LA.

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