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Suramin for germ cell tumors. In vitro growth inhibition and results of a phase II trial
R J Motzer1, E Dmitrovsky, W H Miller
1Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Background:
Several studies have indicated a role for specific growth factors in the differentiation or deregulated growth of germ cell cancers. One proposed mechanism of antitumor activity for suramin is the inhibition of these tumor-derived growth factors.
Methods:
Based on these data, the effects of suramin were studied on the growth of a monolayer culture of two human teratocarcinoma cell lines, NT2/D1 and N2102ep. These represented one cell line that was sensitive (NT2/D1) and one that was resistant (N2102ep) to the differentiation agent retinoic acid. These studies were followed by a Phase II trial of suramin in patients with germ cell tumors. Patients were treated with a continuous infusion of suramin. Dosing was determined by a nomogram based on weekly serum concentrations.
Results:
Suramin inhibited the growth of both cell types in a dose-dependent fashion at a concentration attainable in patient plasma. This provided the rationale for a clinical trial of suramin in patients with cisplatin-refractory germ cell tumors. Fourteen patients were treated, and no complete or partial responses were observed. One patient achieved a prolonged decline in serum alpha-fetoprotein level without change in the size of a bidimensionally measurable retroperitoneal mass for more than 11 months.
Conclusions:
Despite the results of the in vitro studies, a Phase II trial failed to demonstrate significant antitumor activity for suramin in patients with cisplatin-refractory germ cell tumors. Although the dosing of suramin by the nomogram was not associated with neurotoxicity, the time needed to achieve therapeutic levels was lengthy, and the levels, once achieved, were of short duration. Thus, an alternative means of administration, i.e., by intermittent bolus administration, is being investigated in trials for patients with prostatic carcinoma. The lack of definitive efficacy for suramin in this trial has led the authors to consider other agents in Phase II trials for cisplatin-refractory germ cell tumor.
Insights
Suramin showed in vitro anticancer effects but failed in a Phase II trial for germ cell tumors. Further research is needed to explore alternative administration methods for suramin or other agents.
Area of Science:
- Oncology
- Pharmacology
Background:
- Germ cell cancers involve growth factors, with suramin potentially inhibiting tumor-derived factors.
- Suramin's mechanism may involve inhibiting growth factors implicated in germ cell cancer progression.
Purpose of the Study:
- To evaluate suramin's effects on human teratocarcinoma cell lines in vitro.
- To assess suramin's efficacy in a Phase II clinical trial for patients with cisplatin-refractory germ cell tumors.
Main Methods:
- In vitro studies used two human teratocarcinoma cell lines (NT2/D1 and N2102ep) to assess suramin's dose-dependent growth inhibition.
- A Phase II trial administered suramin via continuous infusion, with dosing guided by a nomogram based on weekly serum concentrations in 14 patients.
Main Results:
- Suramin inhibited both cell lines in vitro at achievable plasma concentrations.
- The Phase II trial observed no complete or partial responses in patients with cisplatin-refractory germ cell tumors.
Conclusions:
- Suramin demonstrated limited antitumor activity in patients with cisplatin-refractory germ cell tumors despite promising in vitro results.
- Current continuous infusion dosing achieved therapeutic levels slowly and transiently, prompting investigation into alternative administration methods like intermittent bolus administration.