Cytotoxic conjugates of peptide hormones for cancer chemotherapy

Abstract

A major problem in traditional cancer treatment is the severe toxic side effects of chemotherapy. One approach to increasing drug specificity revolves around the receptors for certain peptide hormones that are aberrantly expressed in many human cancers and peritumoral vessels feeding tumors. This allows some peptides, when used as cytotoxin delivery vectors, to yield conjugates with specific therapeutic advantages, such as rapid tumor cell internalization and tumor-penetrating ability. Thus, peptides can be conjugated with cytotoxic agents which would concentrate in tumor tissue and/or cells through specific peptide-receptor interactions. Overall, this relatively new approach to chemotherapy effectively increases the specificity and efficacy of the cytotoxic agent and should decrease toxic side effects. Peptide hormones such as somatostatin (SST), bombesin (BN), luteinizing hormonereleasing hormone (LHRH) or their analogues have been used as drug delivery vectors when linked with various cytotoxic agents, such as camptothecin (CPT), paclitaxel (PTX) and doxorubicin (DOX). Several lead cytotoxic peptide conjugates have been developed and demonstrate greater cytotoxicity against various cancers together with reduced toxicity to normal tissues. Two examples, JF-10-81 and AN-152, are currently undergoing preclinical and clinical development, respectively. These new cytotoxic peptide conjugates may provide more effective chemotherapy and drug delivery protocols for receptor-specific cancer treatment in the near future.