Summary
VP-16-213 (Etoposide) is an active antineoplastic agent which has undergone extensive evaluation of clinical dose escalation. To corroborate a putative dose-response relationship, we studied, in a modified clonogenic assay, various doses and durations of exposure. VP-16-213 at doses of 0.01, 0.05, 0.10, 0.50, 1.0, 5.0 and 10.0 μg/ml, each with exposure durations of 1, 3, 18, and 30 h, was studied in vitro against two human tumor cell lines, MOLT and 9812. The doses and durations of exposure were chosen to approximate some of the pharmacokinetic values achievable in either standard-dose or high-dose clinical studies. The results, summarized as linear regression lines, demonstrate with statistical significance (p<0.03) that there is correlation between dose and cytotoxicity and between dose x duration of exposure (representing the area under the concentration-time curve) and cytotoxicity. Our in vitro data thus support the concept of intensive use of VP-16-213 to maximize antitumor activity. However, how best to accomplish the manipulation of dose and duration of exposure is not yet clear and will be the subject of future clinical investigations.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aisner J, Van Echo DA, Whitacres M, Wiernik PH (1982) A phase I trial of continuous infusion VP-16-213 (etoposide). Cancer Chemother Pharmacol 7: 157
Creaven PJ (1982) The clinical pharmacology of VM-26 and VP-16-213. A brief overview. Cancer Chemother Pharmacol 7: 133
D'Incalci M, Faring P, Sessa C, Mangioni C, Conter V, Masera G, Rocchetti M, Brambilla Pisoni M, Piazza E, Beer M, Cavalli F (1982) Pharmacokinetics Cancer Chemother Pharmacol 7: 141
Douple EB, Cate CC, Curphey TJ, Pattengill OS, Sorenson GD, Maver LH (1985) Evaluation of drug efficacy in vitro using human small cell carcinoma of the lung spheroids. Cancer 56: 1918
Dow LW, Sinkule JA, Look T, Horvath A, Evans WE (1983) Comparative cytotoxic and cytokinetic effects of the epipodophyllotoxins 4′-demethylepipodophyllotoxin-9-(4,6-O-2-ethylidene-β-D-glucopyranoside) and 4′-demethylepipodophyllotoxin-9-(4,6-O-2-thenylidene-β-D-glucopyranoside) and their metabolites on human leukemic lymphoblasts. Cancer Res 43: 5699
Evans WE, Sinkule JA, Crom WR, Dow L, Look AT, Rivera G (1982) Pharmacokinetics of teniposide (VM-26) and etoposide (VP-16-213) in children with cancer. Cancer Chemother Pharmacolo 7: 147
Hande KR, Wedlund PJ, Noone RM, Wilkinson GR, Greco FA, Wolff SN (1984) Pharmacokinetics of high-dose etoposide (VP-16-213) administered to cancer patients. Cancer Res 44: 379
Issell BF, Crooke S (1979) Etoposide (VP-16-213). Cancer Treat Rep 6: 107–124
Lokich J, Corkery J (1981) Phase I study of VP-16-213 (etoposide) administered as a continuous 5-day infusion. Cancer Treat Rep 65: 887
O'Dwyer PJ, Leyland-Jones B, Alonso MT, Marsoni S, Wittes R (1985) Drug therapy. Etoposide (VP-16-213). Current status of an active anticancer drug. New Engl J Med 312: 692
Postmus PE, Mulder NH, Sleijfer DT, Meinesz AF, Vriesendorp R, deVries EGE (1984) High-dose etoposide for refractory malignancies: a phase I study. Cancer Treat Rep 68: 1471
Radice PA, Bunn PA, Ihde DC (1979) Commentary. Therapeutic trials with VP-16-213 and VM-26: active agents in small cell lung cancer, non-Hodgkin's lymphomas and other malignancies. Cancer Treat Rep 63: 1231
Rozencweig M, Von Hoff DD, Henney JE, Muggia FM (1977) VM-26 and VP-213-16: a comparative analysis. Cancer 40: 334
Salmon SE, Hamburger AW, Soehnlen B, Durie BGM, Alberts DS, Moon TE (1978) Quantitation of differential sensitivity of human tumor stem cells to anticancer drugs. N Engl J Med 298: 1321
Schell FC, Yap HY, Hortobayagi GN, Buzdar AV, Blumenschein GR, Issell B, Esparza L (1981) Phase II study of VP-16-213 in metastatic refractory breast carcinoma. Proc ASCO 22: 357
Sinkule JA, Hutson P, Hayes FA, Etcubanas E, Evans WE (1984) Pharmacokinetics of etoposide (VP-16) in children and adolescents with refractory solid tumors. Cancer Res 44: 3109
Slevin ML, Clark PI, Osborne RJ, Malik S, Wood CD, Harvey VJ, Joel SP, Malpas JS, Wrigley PFM (1986) A randomized trial to evaluate the effect of schedule on the activity of etoposide in small cell lung cancer. Proc ASCO 5: 175
Von Hoff DD (1983) Send this patient's tumor for culture and sensitivity. N Engl J Med 308: 154
Von Hoff DD, Casper J, Bradley E, Jones D, Makuchi R (1981) Association between human tumor colony forming assay results and response of an individual patients tumor to chemotherapy. Am J Med 70: 1027
Von Hoff DD, Clark GM, Stodgill BS, Sarosdy MF (1983) Prospective clinical trial of a human tumor cloning system. Cancer Res 43: 1926
Wolff SN, Fer MF, McKay CM, Hande KR, Hainsworth JD, Greco FA (1983) High-dose VP-16-213 and autologous bone marrow transplantation for refractory malignancies — a phase I study. J Clin Oncol 1: 701
Wolff SN, Johnson DH, Hande KR, Hainsworth JD, Greco FA (1983) High-dose VP-16-213 as single agent chemotherapy for small cell carcinoma of the lung. Cancer Treat Rep 67: 957
Wolff SN, Johnson DH, Hainsworth JD, Greco FA (1984) High-dose VP-16-213 monotherapy for refractory germinal malignancies. J Clin Oncol 2: 271
Wolff SN, Birch R, Sarma P, Greco FA (1986) Randomized dose-response evaluation of etoposide in small cell carcinoma of the lung: a Southeastern Cancer Study Group trial. Cancer Treat Rep 70: 583
Author information
Authors and Affiliations
Additional information
Supported in part by Grant ROI CA39686 from the NIH (KR Hande)
Rights and permissions
About this article
Cite this article
Wolff, S.N., Grosh, W.W., Prater, K. et al. In vitro pharmacodynamic evaluation of VP-16-213 and implications for chemotherapy. Cancer Chemother. Pharmacol. 19, 246–249 (1987). https://doi.org/10.1007/BF00252980
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00252980