Immunological hormone atrophy by gonadotropin‐based drug

Improvement in peptide synthesis have facilitated the development of peptide drugs, especially in the case of short peptides such as gonadotropin releasing hormone (GnRH). Numerous GnRH peptide analogues have been produced, mainly to enhance their affinity to GnRH receptor. A total of 13 luteinizing hormone releasing hormone (LHRH) agonists or antagonists have been used in clinical practice or are in clinical development (Roberts et al. 2004). The progress of genetic engineering technology and bioreactor has made it possible to produce an even wider range of novel substances. Simple ‘cut and copy’ technology has created many new drugs in the pharmaceutical industry. Chimeric proteins are an important example of this. They are usually composed of a targeting motif, which guides another active molecule to tumour cells or to a specific organ. Luteinizing hormone releasing hormone, a short decapeptide, allows toxins to target GnRH receptors positive tumour cells, such as reproductive organs (prostate, breast, ovary and endometrium) (Limonta et al. 2003) and digestive tract neoplasms (Nechushtan et al. 1997). Many reports have demonstrated that the GnRH-based chimeric toxin was targeted specifically to GnRH receptor positive tumour cells and efficiently killed them (FitzGerald et al. 1990; Pai et al. 1992; Haggerty et al. 1999). LHRH–PE40 was one of the recombinant single-chain fusion proteins consisting of the LHRH fused to a binding-defective form of Pseudomonas aeruginosa exotoxin A (PE40). A previous study showed its binding ability to LHRH receptors on human liver cancer cells (Gong et al. 2004). In vitro tests showed that LHRH–PE40 could kill colon carcinoma and hepatocarcinoma (Guangmu et al. 2001). The GnRH studies used short peptides, in either native or modified form, and was very weakly immunogenic. When conjugated to large carrier molecules such as tetanus toxoid and diphtheria toxin, GnRH and its analogues induced antibodies in immunized animals. Antibodies to GnRH interfered with the normal hormone cycle, leading to infertility. Many drugs based on this have been applied in animal science for immunological castration of laboratory animals or pets (Carelli et al. 1982; Bonneau et al. 1994). Theoretically LHRH–PE40, as a chimeric protein of LHRH and PE40, has the potential to impair the male reproductive system. Therefore this report examines the toxicity of long-term use of GnRH based chimeric protein to male adult rats.