Innovative Strategy for the Prevention and Treatment of Metastatic Prostate Cancer: Modified Tetracyclines as Chemotherapeutics

摘要

This is a final report of the funded grant. The overall goal of the project was to investigate the antiproliferative and antimetastatic properties of chemically modified non-antimicrobial tetracycline analogs (CMTs), a new class of targeted drugs against prostate cancer metastatic to bone. This overall goal was achieved. One of the analogues, CMT-3 (also named COL-3, or Metastat) was effective as an anti-proliferative (pro-apoptotic) and anti-metastatic drug suitable for clinical trials. The drug is in a combined Phase II and Phase Ill clinical trials and earned three U.S and many international patents to the PI and his collaborators. In the second phase of the project, the molecular basis of chemoresistance in prostate tumor cells, acquired due to their interaction with stromal cells, and a novel method of combining anti-inflammatory agents and CMT-3 was explored and established. The major findings of the investigation are: (1) CMT-3 and its nitro-derivatives inhibit tumor cell proliferation and invasion by inducing apoptosis, free radical OH generation and cell-cycle arrest (Ref.1- 3); (2) Tumor growth is inhibited by CMTs due to their anti-angiogenic and pro- apoptotic activities (Ref. 2). CMTs inhibit invasion and bone metastasis by inhibition of MMP synthesis, activation and activity and by accumulation in the bone matrix (Ref 1 &3); (3) CMT-3 and COX-2 inhibitors act additively to reduce tumor growth and metastasis; (4) Although no systemic toxicity was observed in pre-clinical models, acute photosensitization at >70 mg/m2 is the major adverse effect on patients (Ref. 4); (5) CMTs could have application in corneal and other diseases (Ref 5).