SELECTIVE CHEMOTHERAPY IN CANCER TREATMENT: Design and Synthesis of Prodrugs
which are Catalytically Activated at the Tumor Site

Doron Shabat

School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences,
Tel Aviv
University, Tel Aviv 69978, Israel

Abstract

Prolonged administration of effective concentrations of chemotherapeutic
agents is usually not possible because of dose-limiting systemic toxicities.
Further more, strong side effects for non-malignant tissues are observed.
Thus, new strategies to target cytotoxic agents specifically to sites of
metastatic cancer are constantly developed. One such strategy to
specifically target chemotherapy to the tumor site by developing of prodrugs
that are inactive when given systemically but become activated upon cleavage
of protecting group. The activation is performed selectively near the tumor
by a specific protein that is secreted or targeted to the cancer cell. To
accomplish this, we intend to design and synthesize a new prodrug, that is
derived from the novel proteasome inhibitor PS-341.The drug will be masked
with a peptide that is specifically hydrolyzable by the prostate specific
antigen, which is active only in the vicinity of prostate tumor cells. In
other targeting approach we have synthesized several prodrugs which are
activated by the catalytic antibody 38C2. The antibody was conjugate to
targeting moieties, which can carry it selectively to the tumor site.
The development of the described prodrugs and testing them in vitro on
cells, will lead the way for in vivo experiments, and will provide a basis
for novel selective chemotherapy treatments for prostate cancer.