title: Clinical trial of continuous infusion verapamil, bolus vinblastine, and continuous infusion VP-16 in drug-resistant pediatric tumors.
abstract: 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 less than 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 determined the maximal-tolerated dose of VPL in a Phase I study and to examine its efficacy in selected relapsed pediatric patients.
authors.affiliation: Division of Hematology-Oncology, Childrens Hospital of Orange County, CA 92668.
authors.forename: M S
authors.initials: MS
authors.lastname: Cairo
authors.forename: S
authors.initials: S
authors.lastname: Siegel
authors.forename: N
authors.initials: N
authors.lastname: Anas
authors.forename: L
authors.initials: L
authors.lastname: Sender
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D005047:Etoposide / Q000008:administration & dosage; D006801:Humans; D007262:Infusions, Intravenous; D007938:Leukemia / Q000188:drug therapy*; D008113:Liver Neoplasms / Q000188:drug therapy*; D009447:Neuroblastoma / Q000188:drug therapy*; D014700:Verapamil / Q000008:administration & dosage; D014747:Vinblastine / Q000008:administration & dosage
chemical_list: D014747:Vinblastine; D005047:Etoposide; D014700:Verapamil