GnRH-based chimeric proteins: future targeting therapy for adenocarcinomas?

As the number of cancer-related deaths has not decreased in recent years, major efforts are being made to find new drugs for cancer treatment. In the past few years many chimeric proteins have been developed to target and kill cancer cells. This class of targeting molecules, designed and constructed by gene fusion techniques, comprises both the cell targeting and the cell killing moieties.

Luteinizing hormone releasing hormone (LHRH), also termed gonadotropin-releasing hormone (GnRH), accounts for the hypothalamic-pituitary gonadal control of human reproduction. The involvement of GnRH has been demonstrated in several carcinomas of hormone-responsive tissues. Exploiting this common feature, we constructed and highly purified Pseudomonas exotoxin (PE)-based chimeric toxins (GnRH-PE), with an eye to targeting those cancer cells bearing GnRH binding sites. In eukaryotic cells, PE enzymaticaly inactivates EF-2 (Elongation Factor-2), thereby arresting protein synthesis and causing cell death. We found that a surprisingly wide variety of cancers, all confined to the adenocarcinoma type, are killed by the GnRH-PE chimeric proteins. We also demonstrated that these chimeric proteins efficiently inhibit cancer growth of well-established colon adenocarcinomas in nude mice.

Because of the immunogenicity and the non-specific toxicity of bacterial toxins such as PE, we have now developed new chimeric proteins, introducing apoptosis-inducing proteins as novel killing components. GnRH-apoptosis-inducing chimeric proteins efficiently inhibited the cell growth of adenocarcinoma cell lines and eventually led to cell death.

The major findings of our studies are the surprisingly widespread presence of GnRH binding sites in human neoplasms-in most of the adenocarcinomas we tested, and the impressive ability of our new GnRH-based chimeric proteins to target and kill such cancer cells both in vitro and in vivo. Therefore, GnRH-based chimeric proteins are the most promising targeting reagents for treatment of human adenocarcinomas.