Prostate cancer is the second-leading cause of cancer death of men in the United States. Current treatments are compromised by adverse side effects. Fortunately, most prostate cancer cells overexpress the prostate-specific membrane antigen (PSMA), whereas the receptor is present at low or undetectable levels in normal cells. This difference could be taken advantage of in order to selectively deliver non-specific cytotoxic drugs to these pathogenic cells while sparing normal cells that lack PSMA, thus improving potencies and reducing toxicities. PSMA is a very attractive therapeutic target that has high affinity for the ligand 2-[3-(1,3-Dicarboxypropyl)-Ureido]Pentanedioic Acid (DUPA) (Ki = 8 nM). After binding to a DUPA-drug conjugate, PSMA internalizes, unloads the conjugate, and returns to the surface. A release mechanism that would facilitate the intracellular cleavage of indenoisoquinoline topoisomerase I inhibitors from their DUPA conjugates was investigated in the present study. A suitable peptide linker was added as a spacer between the drug and the DUPA ligand in order to ensure the binding of PSMA and its ligand. In order to provide preliminary support for this methodology, two indenoisoquinoline topoisomerase I inhibitors and their DUPA conjugates were synthesized and tested in both LNCaP and 22RV1 cell cultures, both of which overexpress PSMA. All of the compounds exhibited GI50 values in the low nanomolar range. The efficacy in an animal model was determined by administering one of the two DUPA-drug conjugates to 22RV1 tumor xenograft-bearing mice, and the results showed a complete cessation of tumor growth and no toxicity (loss of body weight or death of mice) during the treatment period. The results demonstrate that it is possible to selectively target cytotoxic indenoisoquinoline topoisomerase I inhibitors to prostate cancer cells while reducing adverse side effects to normal tissues.

DUPA conjugation of cytotoxic indenoisoquinoline topoisomerase I inhibitors as a method for selectively targeting prostate cancer cells

247th National Meeting (2014)

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