Enhancement of the Antiproliferative Effect of cis-Diamminedichloroplatinum (II) and Other Antitumor Agents by Inhibitors of Enzymes Involved in Growth Factor Signal-Transduction

Abstract

Progress in our understanding of the biochemical basis of malignant growth has led to the identification of new targets in tumor chemotherapy. In many cases the uncontrolled, autonomous growth of transformed cells has been shown to be caused by one of the following mechanisms: (1) autrocrine production of growth factors; (2) expression of constitutively active growth factor receptors; (3) constitutive activation of elements of growth factor signal transduction^1–3. In view of these findings, novel strategies for tumor chemotherapy have been developed including growth factor antagonists⁴ growth factor receptor blockers⁵ and inhibitors of enzymes or ion channels involved in intracellular mitogenic signal transfer. Approaches to interfere with growth factor signal transduction include studies on inhibitors of phospholipase C, protein tyrosine kinases, protein kinase C, Na⁺/H⁺-antiporter and Ca²⁺ antagonists^6,7. A variety of compounds which were developed along these lines of research exhibit remarkable antitumor activity, some of them are less toxic than established, currently employed antitumor agents. With regard to these low toxicity compounds it seemed intriguing to investigate whether their growth inhibitory activity could be combined with the growth inhibition by established antitumor agents. In such a mixture, the combination of the growth inhibitory effects of the components may exhibit an additive or synergistic behaviour. This could be exploited for a less toxic and/or more effective treatment protocol.