Showing papers on "Prinomastat published in 2000"

Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment

Abstract: Experimental studies performed prior to 1990 led to the widely held belief that matrix metalloproteinases (MMPs) produced by cancer cells are of critical importance in tumor invasion and metastasis. Based on this evidence, the pharmaceutical industry produced several well tolerated, orally active MMP inhibitors (MMPIs) which demonstrated efficacy in mouse cancer models. Phase III clinical trials initiated in 1997-98 using marimastat, prinomastat (AG3340), and BAY 12-9566 alone or in combination with standard chemotherapy in patients with advanced cancers (lung, prostate, pancreas, brain, GI tract) have recently been reported; no clinical efficacy was demonstrated. Bayer and Agouron have discontinued their ongoing Phase III drug trials of MMPIs in advanced cancer. In retrospect, the failure of MMPIs to alter disease progression in metastatic cancer might have been anticipated since MMPs appear to be important in early aspects of cancer progression (local invasion and micrometastasis) and may no longer be required once metastases have been established. Our understanding of MMP pathophysiology in cancer has expanded considerably in the past 10 years. Current views indicate that: (1) most MMPs in tumors are made by stromal cells, not carcinoma cells; (2) cancer cells induce stromal cells to synthesize MMPs using extracellular matrix metalloproteinase inducer (EMMPRIN) and cytokine stimulatory mechanisms; and (3) MMPs promote cell migration and the release of growth factors sequestered in the extracellular matrix. MMPs have a dual function in tumor angiogenesis: MMP-2 and MT1-MMP are required in breaking down basement membrane barriers in the early stage of angiogenesis, while other MMPs are involved in the generation of an angiogenic inhibitor, angiostatin. In spite of considerable recent progress in identifying multiple roles of MMPs in disease, our understanding of MMP function in cancer is far from complete (see Table 1). Based on accumulated data, it is recommended that future MMPI trials focus on: (1) patients with early stage cancer; (2) the use of MMPIs along with chemotherapy; (3) the measurement of MMPs in tumor tissue and blood as a means of identifying patients who are more likely to respond to MMPI therapy; and (4) identification of biomarkers that reflect activation or inhibition of MMPs in vivo.

Ongoing trials with matrix metalloproteinase inhibitors

Abstract: Excessive or poorly regulated matrix metalloproteinase (MMP) activity has been implicated as a pathogenic factor in a range of diseases where the extracellular matrix is degraded or remodelled. Synthetic, potent, low molecular weight MMP inhibitors (MMPIs) have been developed and, over the past five years, these agents have begun clinical testing in patients with cancer, rheumatoid arthritis, osteoarthritis and acute macular degeneration. The past year has seen a number of disappointments with the halting of clinical trials of Ro 32-3555 in patients with rheumatoid arthritis and of BAY 12-9566 in patients with cancer. There have, however, been some successes with perhaps the clearest indication of efficacy being seen in the results of a Phase III trial of marimastat in patients with advanced gastric cancer. Clinical trials are continuing with marimastat and other MMPIs, including prinomastat, solimastat, BMS 275291, metastat and neovastat. Results from these trials are expected in the next two years and i...

Clinical Potential of Matrix Metalloprotease Inhibitors in Cancer Therapy

Abstract: Matrix metalloproteases (MMP) are a family of enzymes that contribute to the degradation of the extracellular matrix. The destruction of the extracellular matrix eventually leads to tumour invasion, metastasis and angiogenesis. Realising this mechanism of action, there is tremendous potential for inhibitors of MMP in cancer therapy. Extensive preclinical data have shown that administration of matrix metalloprotease inhibitors (MMPI) to different animal models results in a reduction in primary tumour growth as well as in the number and size of metastatic lesions. Based on promising preclinical studies, synthetic MMPI have been developed and taken into clinical trials. These include marimastat, BAY-129566, CGS-27023A, prinomastat (AG-3340), BMS-275291 and metastat (COL-3). These drugs are all in different stages of clinical development, ranging from phase I to III. In general, musculoskeletal problems, such as joint stiffness and pain in hands, arms and shoulders seem to affect most patients in varying degrees, depending on the dose and type of compound administered. In addition to single agent therapy, several MMPI have entered trials of combination therapy. The objective of combining chemotherapy with an MMPI is to potentiate tumour cytotoxicity as well as to reduce the size and number of metastatic lesions. Several compounds have entered phase III combination therapy trials, but it is still too early to report any data. There is ongoing research in correlating biological end-points, such as levels of MMP and markers of angiogenesis with clinical response. As the field of MMP and their inhibitors continues to mature, its role in cancer therapeutics will be better defined.

Prinomastat, a hydroxamate-based matrix metalloproteinase inhibitor. A novel pharmacological approach for tissue remodelling-related diseases.

Abstract: Prinomastat (formerly AG3340, Agouron Pharmaceuticals, Inc.) is a potent, selective oral inhibitor of matrix metalloproteinase-2, -9, -13 and -14. This peculiar selectivity should represent an advantage for prinomastat in terms of efficacy/tolerability. The drug has been shown to inhibit tumour growth and angiogenesis in a variety of preclinical models, including cancer of colon, breast, lung and intriguingly in melanoma and glioma models. Moreover, the combination of prinomastat and several chemotherapeutic agents was shown to induce additive effects. The drug is currently in Phase III clinical trials for patients with non-small cell lung cancer in combination with paclitaxel and carboplatin, as well as in advanced hormone refractory prostate cancer in combination with mitoxantrone. The most common side effects are musculoskeletal pain and stiffness. These side effects generally cease with treatment interruption. Finally, considering the pathophysiology of MMPs, Agouron is exploring the utility of prinomastat in ophthalmology and dermatology.

The effect of prinomastat (AG3340), a potent inhibitor of matrix metalloproteinases, on a subacute model of proliferative vitreoretinopathy.

Abstract: Purpose To determine the efficacy of prinomastat (AG3340), a synthetic inhibitor of matrix metalloproteinase, in the treatment of experimental proliferative vitreoretinopathy (PVR) induced by intravitreal dispase injection Methods One eye each of 53 New Zealand white rabbits was injected in the vitreous cavity with 007 unit of dispase to induce PVR One week after PVR induction, 53 rabbits were randomized (27:26) to receive 05 mg prinomastat or the vehicle of the drug (acidified water) intravitreally every two weeks The scores of PVR severity (scale of 1–5) were graded to compare the prinomastat-treated animals with the control group Results The average PVR scores in the treatment and control groups were 262 and 357 respectively (p = 0038; Wilcoxon rank sum) Clinically significant PVR with retinal detachment (PVR = grade 3) developed in 76% of rabbits in the control group versus 51% of rabbits treated with prinomastat Conclusions Intravitreally administered prinomastat decreased development

AG-3340 (Agouron Pharmaceuticals Inc).

Abstract: Agouron Pharmaceuticals is developing AG-3340 (prinomastat), the lead compound in a series of structurally related metalloproteinase inhibitors, for the potential treatment of cancer and age-related macular degeneration. AG-3340, an oral, non-peptide inhibitor of gelatinase types A and B (MMP-2 and -9), MT1-MP (MMP-14) and collagenase III [234058], was selected following demonstration of activity in a variety of in vivo preclinical models upon oral dosing. In May 1999, phase III trials for lung and prostate cancers of AG-3340 in front-line combination with chemotherapy was begun in the US and Canada [286380,326640]. The tested dose for these trials is 5 to 15 mg bid. Following demonstration of the enhanced efficacy of chemotherapy when supplemented with AG-3340 in preclinical tumor models, pilot combination studies and double-blinded, placebo-controlled phase III trials in 700 patients are in progress for the treatment of non-small cell lung cancer or advanced hormone-refractory prostate cancer [302584,327014]. In August 1999, Agouron initiated a second, confirmatory phase III trial of AG-3340 in combination with chemotherapy in patients with advanced non-small cell lung cancer [337253]. Pharmacokinetic studies have been conducted in healthy male volunteers and single agent dose-escalation studies in patients demonstrated toxicities (grade 1 or 2; joint related) were not doselimiting [302238]. At the 10th European Organization for Research and Treatment of Cancer (EORTC) meeting in Amsterdam (June 1998), Agouron released encouraging results from two phase I studies and one preclinical study of AG-3340 [289688]. In a further 15- patient, phase I study of AG-3340 with paclitaxel and carboplatin, the combination was safe and well tolerated [326268]. AG-3340 has demonstrated significant antimetastatic and antitumor activity in animal models, as well as oral bioavailability and a favorable pharmacokinetic profile. Daily doses of 50 mg/kg completely halted growth of Lewis lung carcinomas in two thirds of test animals and reduced the formation of lung metastasis (0.5 mm in diameter) by 90% [205708]. In December 1997, Roche announced it would discontinue its cancer R&D collaborations with Agouron on AG-3340 as it did not fulfill its scientific and business objectives [271723]. Agouron is investigating analogs of AG-3340 which are undergoing animal studies [332841].