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 anti‐MMP agents tested, CMT‐3 (6‐deoxy, 6‐demethyl,4‐de‐dimethylamino tetracycline) showed highest activity against CaP cell invasion and cell proliferation. Micromolar concentration of CMT‐3 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, CMT‐3 and DC both reduced the lung metastases (> 50%). CMT‐3, 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 CMT‐3 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 CMT‐3 for the treatment of metastatic disease

Late‐stage calcites in the Permian Capitan Formation and its equivalents, Delaware Basin margin, west Texas and New Mexico: evidence for replacement of precursor evaporites

Comparison of Upper Guadalupian fore‐reef, reef and back‐reef strata from outcrops in the Guadalupe Mountains with equivalent subsurface cores from the northern and eastern margins of the Delaware Basin indicates that extensive evaporite diagenesis has occurred in both areas. In both surface and subsurface sections, the original sediments were extensively dolomitized and most primary and secondary porosity was filled with anhydrite. These evaporites were emplaced by reflux of evaporitic fluids from shelf settings through solution‐enlarged fractures and karstic sink holes into the underlying strata. Outcrop areas today, however, contain no preserved evaporites in reef and fore‐reef sections and only partial remnants of evaporites are retained in back‐reef settings. In their place, these rocks contain minor silica, very large volumes of coarse sparry calcite and some secondary porosity. The replacement minerals locally form pseudomorphs of their evaporite precursors and, less commonly, contain solid anhydrite inclusions. Some silicification, dissolution of anhydrite and conversion of anhydrite to gypsum have occurred in these strata where they are still buried at depths in excess of 1 km; however, no calcite replacements were noted from any subsurface core samples. Subsurface alteration has also led to the widespread, late‐stage development of large‐ and small‐scale dissolution breccias. The restriction of calcite cements to very near‐surface sections, petrographic evidence that the calcites post‐date hydrocarbon emplacement, and the highly variable but generally ‘light’carbon and oxygen isotopic signatures of the spars all indicate that calcite precipitation is a very late diagenetic (telogenetic) phenomenon. Evaporite dissolution and calcitization reactions have only taken place where Permian strata were flushed with meteoric fluids as a consequence of Tertiary uplift, tilting and breaching of regional hydrological seals. A typical sequence of alteration involves initial corrosion of anhydrite, one or more stage