EXECUTIVE SUMMARY

Peptide Aminoarylmethyl Conjugates of Cytotoxic Agents

for Targeted Cancer Chemotherapy

SUMMARY:  Prof. Long Hu in the Department of Pharmaceutical Chemistry at Rutgers University has prepared peptide conjugates of chemotherapeutic agents that are designed so that the chemotherapeutic agent is inactive until the conjugate is cleaved by a tumor-specific enzyme in close proximity to tumor tissues.  This increases the selectivity of the chemotherapeutic agent in killing cancer cells while decreasing the adverse side effects elsewhere in the system.  Siuta Consulting has been retained by Rutgers to find partners for this technology.

BACKGROUND:  One of the big challenges in cancer chemotherapy is the development of therapeutics that will specifically target cancer cells vs normal cells, thereby eliminating or substantially reducing the commonly observed toxic side effects.  Research by Prof. Hu elegantly addresses this challenge by utilizing a prodrug version of some of the established chemotherapeutic agents thereby making them available in the active form only at the target tumor site.

TECHNOLOGY:  Cyclophosphamide is an anticancer drug currently used in the treatment of a variety of tumors.  It is administered in an inactive form that is activated by the liver cytochrome P-450 pathway.  After activation, cytotoxic metabolites including phosphoramide mustard, form DNA crosslinks between (interstrand crosslinkages) and within (intrastrand crosslinkages) DNA strands at guanine N-7 positions, leading to cell death.  While the cytotoxic metabolites produce the desired anticancer effect in tumor tissues, they are also distributed to normal tissues causing adverse side effects. 

To reduce the adverse side effects of cyclophosphamide, Prof. Hu has created a peptide conjugate using phosphoramide mustard, the active metabolite of cyclophosphamide.  The conjugate is designed to be proteolytically cleaved by the tumor-specific enzyme, prostate-specific antigen (PSA) at the tumor site.  Upon cleavage, the conjugate undergoes spontaneous elimination of phosphoramide mustard leading to the site-specific release of the cytotoxic agent. The peptide phosphoramide mustard prodrugs have been shown to selectively target PSA-producing prostate cancer cells in vitro and are in the process of being evaluated in vivo for selective antiproliferative activity in a mouse xenograft model of prostate cancer.