4 research outputs found
Interaction between Stromal Cells and Tumor Cells Induces Chemoresistance and Matrix Metalloproteinase Secretion
MMP Inhibition in Prostate Cancer
Matrix metalloproteinases (MMPs) play a significant role during the development and metastasis of prostate cancer (CaP). CaP cells secrete high levels of MMPs and low levels of endogenous MMP inhibitors (TIMPs), thus creating an excess balance of MMPs. Established CaP cell lines that express high levels of MMPs frequently metastasize to the bone and the lungs. Drugs such as Taxol and alendronate that reduce cell motility and calcium metabolism reduce bony metastasis of xenografted CaP tumors. We tested several synthetic, nontoxic inhibitors of MMPs that can be administered orally, including doxycycline (DC) and chemically modified tetracyclines (CMTs) on CaP cells in vitro and on a rat CaP model in vivo. Among several antiâMMP agents tested, CMTâ3 (6âdeoxy, 6âdemethyl,4âdeâdimethylamino tetracycline) showed highest activity against CaP cell invasion and cell proliferation. Micromolar concentration of CMTâ3 and DC inhibited both the secretion and activity of MMPs by CaP cells. When tested for in vivo efficacy in the Dunning rat CaP model by daily oral gavage, CMTâ3 and DC both reduced the lung metastases (> 50%). CMTâ3, but not DC, inhibited tumor incidence (55 ± 9%) and also reduced the tumor growth rate (27 ± 9.3%). More significantly, the drugs showed minimum systemic toxicity. Ongoing studies indicate that CMTâ3 may inhibit the skeletal metastases of CaP cells and delay the onset of paraplegia due to lumbar metastases. These preclinical studies provide the basis for clinical trials of CMTâ3 for the treatment of metastatic disease