metastat and Neoplasms

Matrix metalloproteinases belong to a diverse group of enzymes that are not only involved in restructuring the extracellular matrix, but also play a major role in various pathophysiological conditions by virtue of their complicated expression, activation, and regulation processes. They have been widely implicated to function as major contenders in cancer progression, frequently due to their role in invasion, proliferation and metastasis. MMP inhibitors have been specifically designed to target these altered activities of MMPs, mostly by means of inhibiting their function and by diminishing their increased expression in various disease states, particularly cancer. Tetracyclines and chemically modified tetracyclines (CMTs) have been rationally designed to inhibit the activity of MMPs and thus decrease the potential risk of spread of tumor cells to distant sites by invasion and metastasis. Pre-clinical and early clinical data for one of these CMTs, COL-3 (formerly CMT-3) indicate considerable potential for this group of anticancer agents. Further testing and rational modifications of these CMT analogues might lead to new anticancer agents.

Topics: Animals; Antineoplastic Agents; Enzyme Activation; Enzyme Inhibitors; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasms; Tetracyclines

CMT-3 is an orally active matrix metalloprotease inhibitor, and one of a series of inhibitors of multiple proteases and cytokines, under development by CollaGenex. The compound is currently undergoing phase II trials for the potential treatment of cancer, in particular metastatic cancer and HIV-related Kaposi's sarcoma.

Topics: Animals; Clinical Trials as Topic; Drugs, Investigational; Enzyme Inhibitors; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasms; Technology, Pharmaceutical; Tetracyclines

The matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation of the extracellular matrix. The MMPs have been implicated in the processes of tumor growth, invasion, and metastasis; are frequently overexpressed in malignant tumors; and have been associated with an aggressive malignant phenotype and adverse prognosis in patients with cancer. A number of MMP inhibitors are being developed for the treatment of cancer. The most extensively studied class of MMP inhibitors includes collagen peptidomimetics and nonpeptidomimetic inhibitors of the MMP active site, tetracycline derivatives, and bisphosphonates. The hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat, which bind covalently to the zinc atom at the MMP-active site, were the first MMP inhibitors to be studied in detail. Marimastat is currently being studied in randomized clinical trials. The nonpeptidic MMP inhibitors were synthesized in an attempt to improve the oral bioavailability and pharmaceutical properties of the peptidic inhibitors. Several members of this class of compounds are undergoing evaluation in phase III clinical trials. The tetracyclines and, particularly, the nonantibiotic chemically modified tetracyclines, interfere with several aspects of MMP expression and activation and inhibit tumor growth and metastases in preclinical models. A representative agent of this class, Col-3, is currently undergoing phase I clinical trials. The development of the MMP inhibitors, like that of other targeted and predominantly antiproliferative compounds, poses a challenge because the paradigms that have governed the design of clinical oncology trials may not be relevant to this new class of agents. The anticipated need for long-term administration of these drugs, together with their cytostatic mechanism of action, will require novel clinical trial design strategies.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Biphenyl Compounds; Clinical Trials as Topic; Drugs, Investigational; Enzyme Inhibitors; Humans; Hydroxamic Acids; Imidazoles; Matrix Metalloproteinase Inhibitors; Neoplasms; Organic Chemicals; Phenylalanine; Phenylbutyrates; Protease Inhibitors; Pyrazines; Sulfonamides; Tetracycline; Tetracyclines; Thiophenes

The purpose of this research was to assess the feasibility of administering Col-3, an oral chemically modified tetracycline derivative with potent inhibitory effects on matrix metalloproteinase activity and production, and recommend a dose on an uninterrupted once-daily schedule. The study also sought to characterize the pharmacokinetic behavior of Col-3 and seek evidence of anticancer activity.. Patients with advanced solid malignancies were treated with escalating doses of Col-3 with dose level assignment according to an accelerated titration scheme. Because photosensitivity skin reactions were being reported in concurrent trials of Col-3, patients were instructed to apply sunscreen rigorously throughout the trial. The maximum tolerated dose was defined as the highest dose at which <2 of the first 6 new patients experienced dose-limiting toxicity. The pharmacokinetic behavior of Col-3 was characterized, and pharmacodynamic relationships were sought.. Thirty-three patients were treated with 73 courses of Col-3 at four dose levels ranging from 36 to 98 mg/m2/day. Unacceptably high incidences of photosensitivity skin reactions and malaise were noted in the first 28-day courses of patients treated with Col-3 at doses exceeding 50 mg/m2/day. At 50 mg/m2/day, severe toxicity occurred in 2 of 12 new patients in first courses, and no additional dose-limiting toxicities were observed in subsequent courses. Other mild to modest adverse effects included nausea, vomiting, liver function tests abnormalities, diarrhea, mucositis, leukopenia, and thrombocytopenia. The pharmacokinetics of Col-3 were dose proportional, and mean trough concentrations at steady state were similar to biologically relevant concentrations in preclinical studies. Major responses did not occur, but durable disease stability was noted in 3 patients, one each with carcinosarcoma of the uterus, pancreas, and ovary, all of whom had experienced disease progression before Col-3 treatment.. The recommended dose for Phase II studies of Col-3 administered once daily on an uninterrupted schedule is 50 mg/m2/day accompanied by efforts that promote adherence to the use of sunscreen and other photoprotective measures. Pharmacokinetic results indicate that plasma concentrations above biologically relevant concentrations are readily maintained at this dose, and additional disease-directed studies, particularly in patients with soft tissue sarcoma, should be considered.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Agents; Area Under Curve; Dose-Response Relationship, Drug; Fatigue; Female; Humans; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Metabolic Clearance Rate; Middle Aged; Nausea; Neoplasms; Tetracyclines; Treatment Outcome

This phase I clinical trial was designed to determine the maximum-tolerated dose and dose-limiting toxicities of the matrix metalloproteinase (MMP) inhibitor COL-3 in patients with refractory solid tumors.. Thirty-five patients with different cancer types were enrolled. COL-3 doses were escalated from 36 mg/m2/d in successive cohorts of at least three patients. Circulating levels of MMP-2, MMP-9, vascular endothelial growth factor, and basic fibroblast growth factor were assessed during treatment. Pharmacokinetic parameters were assessed for single and multiple doses of drug.. Cutaneous phototoxicity was dose-limiting at 98 mg/m2/d. With the use of prophylactic sunblock, COL-3 was well tolerated at 70 mg/m2/d. The dose of 36 mg/m2/d was well tolerated without the use of sunblock. Other toxicities that did not seem to be related to dose or pharmacokinetics included anemia, anorexia, constipation, dizziness, elevated liver function test results, fever, headache, heartburn, nausea, vomiting, peripheral and central neurotoxicities, fatigue, and three cases of drug-induced lupus. Disease stabilization for periods of 26+ months, 8 months, and 6 months were seen in hemangioendothelioma, Sertoli-Leydig cell tumor, and fibrosarcoma, respectively. There was a potentially statistically significant relationship between changes in plasma MMP-2 levels and cumulative doses of drug when progressive disease patients were compared with those with stable disease or toxicity (P = .042).. COL-3 induced disease stabilization in several patients who had a nonepithelial type of malignancy. Phototoxicity was dose-limiting. We recommend the dose of 36 mg/m2/d for phase II trials.

Topics: Adult; Aged; Antineoplastic Agents; Endothelial Growth Factors; Enzyme Inhibitors; Female; Fibroblast Growth Factor 2; Humans; Lymphokines; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Middle Aged; Neoplasms; Statistics, Nonparametric; Tetracyclines; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Topics: Antineoplastic Agents; Chemistry, Pharmaceutical; Deoxycytidine; Doxycycline; Drug Industry; Drug Synergism; Gemcitabine; Hexanones; Humans; Neoplasms; Tetracyclines

Aggressive melanoma cells have been shown to overexpress proteins that modify their environment, but these proteins can be inhibited by a chemically modified tetracycline.

Topics: Environment; Humans; Neoplasms; Protein Biosynthesis; Proteins; Tetracycline; Tetracyclines