We have approached oral carcinogenesis by initially searching for evidence of activated tyrosine kinases in naturally occurring human neoplasia, especially squamous cell carcinomas of the head and neck. Initial results have shown that the receptor for epidermal growth factor (EGF) is activated in a number of oral cavity tumors. As a probe for the mechanism of this activation, we have investigated the effect of suramin treatment on EGF receptor activity. It was expected that suramin would greatly reduce the level of intracellular protein-tyrosine phosphorylation by the EGF receptor. Instead, the drug dramatically enhanced protein-tyrosine phosphorylation in epithelial cell tumors. The mechanism at play was shown to involve activation of the growth factor, namely transforming growth factor alpha, that in turn stimulates the tyrosine kinase activity of the EGF receptor. These results suggested that suramin may stimulate the growth of certain tumors, and indeed suramin enhances the growth of oral carcinoma cells in culture. Cancer patients receiving suramin chemotherapy currently are being examined for expression of TGFalpha.