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Eric F Johnson - One of the best experts on this subject based on the ideXlab platform.

  • contributions of ionic interactions and protein dynamics to cytochrome p450 2d6 cyp2d6 substrate and inhibitor binding
    Journal of Biological Chemistry, 2015
    Co-Authors: A Wang, C D Stout, Qinghai Zhang, Eric F Johnson
    Abstract:

    P450 2D6 contributes significantly to the metabolism of >15% of the 200 most marketed drugs. Open and closed crystal structures of P450 2D6 thioridazine complexes were obtained using different crystallization conditions. The protonated piperidine moiety of thioridazine forms a charge-stabilized hydrogen bond with Asp-301 in the active sites of both complexes. The more open conformation exhibits a second molecule of thioridazine bound in an expanded substrate access channel antechamber with its piperidine moiety forming a charge-stabilized hydrogen bond with Glu-222. Incubation of the crystalline open thioridazine complex with alternative ligands, Prinomastat, quinidine, quinine, or ajmalicine, displaced both thioridazines. Quinine and ajmalicine formed charge-stabilized hydrogen bonds with Glu-216, whereas the protonated nitrogen of quinidine is equidistant from Asp-301 and Glu-216 with protonated nitrogen H-bonded to a water molecule in the access channel. Prinomastat is not ionized. Adaptations of active site side-chain rotamers and polypeptide conformations were evident between the complexes, with the binding of ajmalicine eliciting a closure of the open structure reflecting in part the inward movement of Glu-216 to form a hydrogen bond with ajmalicine as well as sparse lattice restraints that would hinder adaptations. These results indicate that P450 2D6 exhibits sufficient elasticity within the crystal lattice to allow the passage of compounds between the active site and bulk solvent and to adopt a more closed form that adapts for binding alternative ligands with different degrees of closure. These crystals provide a means to characterize substrate and inhibitor binding to the enzyme after replacement of thioridazine with alternative compounds.

  • crystal structure of human cytochrome p450 2d6 with Prinomastat bound
    Journal of Biological Chemistry, 2012
    Co-Authors: A Wang, Uzen Savas, Meihui Hsu, David C Stout, Eric F Johnson
    Abstract:

    Human cytochrome P450 2D6 contributes to the metabolism of >15% of drugs used in clinical practice. This study determined the structure of P450 2D6 complexed with a substrate and potent inhibitor, Prinomastat, to 2.85 A resolution by x-ray crystallography. Prinomastat binding is well defined by electron density maps with its pyridyl nitrogen bound to the heme iron. The structure of ligand-bound P450 2D6 differs significantly from the ligand-free structure reported for the P450 2D6 Met-374 variant (Protein Data Bank code 2F9Q). Superposition of the structures reveals significant differences for β sheet 1, helices A, F, F′, G″, G, and H as well as the helix B-C loop. The structure of the ligand complex exhibits a closed active site cavity that conforms closely to the shape of Prinomastat. The closure of the open cavity seen for the 2F9Q structure reflects a change in the direction and pitch of helix F and introduction of a turn at Gly-218, which is followed by a well defined helix F′ that was not observed in the 2F9Q structure. These differences reflect considerable structural flexibility that is likely to contribute to the catalytic versatility of P450 2D6, and this new structure provides an alternative model for in silico studies of substrate interactions with P450 2D6.

A Wang - One of the best experts on this subject based on the ideXlab platform.

  • contributions of ionic interactions and protein dynamics to cytochrome p450 2d6 cyp2d6 substrate and inhibitor binding
    Journal of Biological Chemistry, 2015
    Co-Authors: A Wang, C D Stout, Qinghai Zhang, Eric F Johnson
    Abstract:

    P450 2D6 contributes significantly to the metabolism of >15% of the 200 most marketed drugs. Open and closed crystal structures of P450 2D6 thioridazine complexes were obtained using different crystallization conditions. The protonated piperidine moiety of thioridazine forms a charge-stabilized hydrogen bond with Asp-301 in the active sites of both complexes. The more open conformation exhibits a second molecule of thioridazine bound in an expanded substrate access channel antechamber with its piperidine moiety forming a charge-stabilized hydrogen bond with Glu-222. Incubation of the crystalline open thioridazine complex with alternative ligands, Prinomastat, quinidine, quinine, or ajmalicine, displaced both thioridazines. Quinine and ajmalicine formed charge-stabilized hydrogen bonds with Glu-216, whereas the protonated nitrogen of quinidine is equidistant from Asp-301 and Glu-216 with protonated nitrogen H-bonded to a water molecule in the access channel. Prinomastat is not ionized. Adaptations of active site side-chain rotamers and polypeptide conformations were evident between the complexes, with the binding of ajmalicine eliciting a closure of the open structure reflecting in part the inward movement of Glu-216 to form a hydrogen bond with ajmalicine as well as sparse lattice restraints that would hinder adaptations. These results indicate that P450 2D6 exhibits sufficient elasticity within the crystal lattice to allow the passage of compounds between the active site and bulk solvent and to adopt a more closed form that adapts for binding alternative ligands with different degrees of closure. These crystals provide a means to characterize substrate and inhibitor binding to the enzyme after replacement of thioridazine with alternative compounds.

  • crystal structure of human cytochrome p450 2d6 with Prinomastat bound
    Journal of Biological Chemistry, 2012
    Co-Authors: A Wang, Uzen Savas, Meihui Hsu, David C Stout, Eric F Johnson
    Abstract:

    Human cytochrome P450 2D6 contributes to the metabolism of >15% of drugs used in clinical practice. This study determined the structure of P450 2D6 complexed with a substrate and potent inhibitor, Prinomastat, to 2.85 A resolution by x-ray crystallography. Prinomastat binding is well defined by electron density maps with its pyridyl nitrogen bound to the heme iron. The structure of ligand-bound P450 2D6 differs significantly from the ligand-free structure reported for the P450 2D6 Met-374 variant (Protein Data Bank code 2F9Q). Superposition of the structures reveals significant differences for β sheet 1, helices A, F, F′, G″, G, and H as well as the helix B-C loop. The structure of the ligand complex exhibits a closed active site cavity that conforms closely to the shape of Prinomastat. The closure of the open cavity seen for the 2F9Q structure reflects a change in the direction and pitch of helix F and introduction of a turn at Gly-218, which is followed by a well defined helix F′ that was not observed in the 2F9Q structure. These differences reflect considerable structural flexibility that is likely to contribute to the catalytic versatility of P450 2D6, and this new structure provides an alternative model for in silico studies of substrate interactions with P450 2D6.

William R. Freeman - One of the best experts on this subject based on the ideXlab platform.

  • the effect of Prinomastat ag3340 a potent inhibitor of matrix metalloproteinase on a new animal model of epiretinal membrane
    Retina-the Journal of Retinal and Vitreous Diseases, 2004
    Co-Authors: Mohamed H Elbradey, Dirk-uwe Bartsch, Lingyun Cheng, Michael Niessman, Abbas Elmusharaf, William R. Freeman
    Abstract:

    Purpose: To develop a simple epiretinal membrane (ERM) animal model and evaluate the efficacy of Prinomastat (AG3340), a synthetic inhibitor of matrix metalloproteinase. Methods: This experiment was carried out on 18 eyes of nine Brown Norway rats. Preretinal hemorrhage was induced bilaterally using diode laser focused deeply on choroidal blood vessels. One day later, AG3340 was injected intravitreally in the right eyes while the left eyes received equal amounts of vehicle. The developed epiretinal membrane was measured in disk areas and compared between groups. Results: Clinically, preretinal hemorrhage showed a slow clearance persisting for 8 to 10 weeks. ERM was well established around 12 weeks. Histologically, ERMs consist of fibroblast and glial cells embedded in collagen-rich extracellular matrix infiltrated by macrophages. Seventy-five percent of the hemorrhagic laser burns in the control group developed ERM, whereas only 25% of the hemorrhagic laser burns in treated group developed ERM (P = 0.01). The total surface area of developed ERM was 3.66 DD in treated eyes versus 25.45 DD in control eyes (P = 0.049). The mean surface area of ERM per eye was 0.52 disk areas ± 1.05 in treated eyes versus 3.18 ± 3.07 in control eyes. Conclusion: We demonstrated that ERM can be induced on rat retina by simple hemorrhagic retinal laser coagulation. This new animal model could be used for future evaluation of different medical treatment modalities for proliferating ERM. Furthermore, AG3340 demonstrated an inhibitory effect on ERM formation in this new rat model.

  • Efficacy of Prinomastat) (AG3340), a matrix metalloprotease inhibitor, in treatment of retinal neovascularization.
    Current Eye Research, 2002
    Co-Authors: Claudio R. Garcia, Dirk-uwe Bartsch, Maria E. Rivero, Martin Hagedorn, Charles D. Mcdermott, Germaine Bergeron-lynn, Lingyun Cheng, Krzysztof Appelt, William R. Freeman
    Abstract:

    Purpose. To study the activity of the novel anti-angiogenic compound AG3340 (Prinomastat ®) , a selective inhibitor of matrix metalloproteases, in an animal model of retinal neovascularization. Methods. C57BL/6J mice were used to produce oxygen-induced retinal neovascularization. Mice were exposed to room air from birth (P0) to postnatal 7 days (P7) and to hyperoxia (75% oxygen) for the next 5 days. On postnatal day 12 (P12) the animals were returned to the room air and were treated until postnatal day 16 (P16) with intraperitoneal injections of AG 3340. Four groups were assigned: no drug, 1.6 mg/kg/day, 16 mg/kg/day and 48 mg/kg/day. On day 17 (P17) the animals were sacrificed and the eyes prepared for histological sectioning. Preretinal neovascularization was assessed by counting neovascular nuclei of endothelial cells in the preretinal side of the internal limiting membrane (ILM). The use of animals for this study complies with the ARVO guidelines for animal research. Results. AG3340 administered syste...

  • the effect of Prinomastat ag3340 a synthetic inhibitor of matrix metalloproteinases on uveal melanoma rabbit model
    Current Eye Research, 2002
    Co-Authors: Ugur Ozerdem, Krzysztof Appelt, Beata Machhofacre, Nissi Varki, Robert Folberg, A J Mueller, Renata Ochabski, Tony Pham, William R. Freeman
    Abstract:

    Purpose. We studied the effects of intravitreally administered Prinomastat on the take rate and growth of uveal melanoma after xenograft implantation in rabbit uveal melanoma model. Methods. Uveal melanoma xenograft was implanted to suprachoroidal space in each eye of 24 pigmented rabbits which were immunosuppressed with cyclosporine. One week after surgery, the eyes were randomized to receive Prinomastat or the vehicle of the Prinomastat intravitreally every week for 4 weeks. The take rate of the xenograft, tumor height, apoptosis, and necrosis in the eyes which developed tumors from the treatment and control groups were compared. Results. A tumor mass was identified in 8 of 24 (33%) Prinomastat-treated eyes and 20 of 24 (83%) of the vehicle-treated eyes. Echographic mesurements revealed a mean tumor height of 2.2 mm in the Prinomastat-treated group and 3.8 mm in the control group in those eyes with take of tumor (p < 0.001). Stereomicroscopic measurements showed a mean tumor height of 1.9 mm in the t...

  • the effect of Prinomastat ag3340 a synthetic inhibitor of matrix metalloproteinases on posttraumatic proliferative vitreoretinopathy
    Ophthalmic Research, 2001
    Co-Authors: Ugur Ozerdem, Krzysztof Appelt, Beata Machhofacre, Kelly S Keefe, Tony Pham, Kelly A Soules, William R. Freeman
    Abstract:

    In a search for a pharmacologic adjuvant in the management of posttraumatic proliferative vitreoretinopathy (PVR), we investigated the effect of intravitreal injection of Prinomastat (AG3340) on an experimental model. Posterior penetrating eye trauma was created in one eye each of 24 New Zealand white rabbits. One week after the surgery, all rabbits were randomized (1:1) to receive 0.5 mg Prinomastat or the vehicle of the drug intravitreally every week for 6 weeks. The degree of PVR for each hemiretina was scored, and the two scores were summed to obtain a total eye score. The mean total eye score was 3.58 in the treatment group and 5.75 in the control group (p = 0.0307). The numbers of eyes with tractional retinal detachment in the Prinomastat-treated (n = 12) and control (n = 12) groups were 3 and 9, respectively (p = 0.0391). These results suggest that intravitreally administered Prinomastat has an inhibitory effect on posttraumatic PVR.

  • the effect of Prinomastat ag3340 a potent inhibitor of matrix metalloproteinases on a subacute model of proliferative vitreoretinopathy
    Current Eye Research, 2000
    Co-Authors: Ugur Ozerdem, Charles D. Mcdermott, Lingyun Cheng, Krzysztof Appelt, Beata Machhofacre, Sunan Chaidhawangul, Kelly S Keefe, Germaine Bergeronlynn, William R. Freeman
    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 0.07 unit of dispase to induce PVR. One week after PVR induction, 53 rabbits were randomized (27:26) to receive 0.5 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 2.62 and 3.57 respectively (p = 0.038; 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 ...

David R Shalinsky - One of the best experts on this subject based on the ideXlab platform.

  • magnetic resonance imaging detects early changes in microvascular permeability in xenograft tumors after treatment with the matrix metalloprotease inhibitor Prinomastat
    Technology in Cancer Research & Treatment, 2004
    Co-Authors: Marlene Wiart, L Fournier, Viktor Novikov, David M Shames, Timothy P L Roberts, David R Shalinsky, Robert C Brasch
    Abstract:

    Macromolecular contrast medium-enhanced magnetic resonance imaging was applied to monitor the effect of matrix metalloprotease (MMP) inhibition on microvascular characteristics of human breast cancers implanted in athymic rats. Twice-daily intraperitoneal administration of Prinomastat over 1.5 days induced significant declines in MRI-assayed microvascular permeabilities (p<0.05); but this leak suppression effect had extinguished by the 10th day of MMP treatment using the same dose and time schedule. Results demonstrate that Prinomastat produces a rapid but transient decrease in tumor vascular permeability. Contrast-enhanced MRI using macromolecular contrast medium may prove useful as a biomarker for the dynamic MMP biological effect in cancers.

  • the matrix metalloproteinase inhibitor Prinomastat enhances photodynamic therapy responsiveness in a mouse tumor model
    Cancer Research, 2004
    Co-Authors: Angela Ferrario, David R Shalinsky, Christophe F Chantrain, Hiroyuki Shimada, Yves A Declerck, Karl Von Tiehl, S Buckley, Natalie Rucker, Charles J Gomer
    Abstract:

    Photodynamic therapy (PDT) clinical results are promising; however, tumor recurrences can occur and, therefore, methods for improving treatment efficacy are needed. PDT elicits direct tumor cell death and microvascular injury as well as expression of angiogenic, inflammatory, and prosurvival molecules. Preclinical studies combining antiangiogenic drugs or cyclooxygenase-2 inhibitors with PDT show improved treatment responsiveness (A. Ferrario et al., Cancer Res 2000;60:4066-9; A. Ferrario et al., Cancer Res 2002;62:3956-61). In the present study, we evaluated the role of Photofrin-mediated PDT in eliciting expression of matrix metalloproteinases (MMPs) and modulators of MMP activity. We also examined the efficacy of a synthetic MMP inhibitor, Prinomastat, to enhance tumoricidal activity after PDT, using a mouse mammary tumor model. Immunoblot analysis of extracts from PDT-treated tumors demonstrated strong expression of MMPs and extracellular MMP inducer along with a concomitant decrease in expression of tissue inhibitor of metalloproteinase-1. Gelatin zymography and enzyme activity assays performed on protein extracts from treated tumors confirmed the induction of both latent and enzymatically active forms of MMP-9. Immunohistochemical analysis indicated that infiltrating inflammatory cells and endothelial cells were primary sources of MMP-9 expression after PDT, whereas negligible expression was observed in tumor cells. Administration of Prinomastat significantly improved PDT-mediated tumor response (P = 0.02) without affecting normal skin photosensitization. Our results indicate that PDT induces MMPs and that the adjunctive use of an MMP inhibitor can improve PDT tumor responsiveness.

  • stromal matrix metalloproteinase 9 regulates the vascular architecture in neuroblastoma by promoting pericyte recruitment
    Cancer Research, 2004
    Co-Authors: Christophe F Chantrain, David R Shalinsky, Hiroyuki Shimada, Sonata Jodele, Susan Groshen, Zena Werb, Lisa M Coussens, Yves A Declerck
    Abstract:

    Advanced stages of neuroblastoma show increased expression of matrix metalloproteinases MMP-2 and MMP-9 (Y. Sugiura et al ., Cancer Res., 58: 2209–2216, 1998) that have been implicated in many steps of tumor progression, suggesting that they play a contributory role. Using pharmacological and genetic approaches, we have examined the role of these MMPs in progression of SK-N-BE (2).10 human neuroblastoma tumors orthotopically xenotransplanted into immunodeficient mice. Mice treated with Prinomastat, a synthetic inhibitor of MMPs, showed an inhibition of tumor cell proliferation in implanted tumors and a prolonged survival (50 versus 39 days in control group, P < 0.035). Treatment with Prinomastat did not affect formation of liver metastases ( P = 0.52) but inhibited intravascular colonization by the tumor cells in the lung by 73.8% ( P = 0.03) and angiogenesis in both primary tumors and experimental liver metastases. The primary tumors from Prinomastat-treated mice showed a 39.3% reduction in endothelial area detected by PECAM/CD31 staining in tumor sections ( P < 0.001), primarily due to the presence of smaller vessels ( P = 0.004). MMP-2 is expressed by neuroblastoma tumor cells and stromal cells, whereas MMP-9 is exclusively expressed by stromal cells, particularly vascular cells. To examine the contribution of MMP-9 to tumor angiogenesis, we generated RAG1/MMP-9 double-deficient mice. We observed a significant inhibition of angiogenesis in the immunodeficient RAG1/MMP-9 double-deficient mice orthotopically implanted with tumor cells ( P = 0.043) or implanted s.c. with a mixture of tumor cells and Matrigel ( P < 0.001). Using an FITC-labeled lectin, we demonstrated an inhibition in the architecture of the tumor vasculature in MMP-9-deficient mice, resulting in fewer and smaller blood vessels. These changes were associated with a 48% decrease in pericytes present along microvessels. Taken together, the data demonstrate that in neuroblastoma, stromally derived MMP-9 contributes to angiogenesis by promoting blood vessel morphogenesis and pericyte recruitment.

  • early combined treatment with carboplatin and the mmp inhibitor Prinomastat prolongs survival and reduces systemic metastasis in an aggressive orthotopic lung cancer model
    Lung Cancer, 2003
    Co-Authors: Jiang Liu, David R Shalinsky, Mingsound Tsao, Marco Pagura, Rama Khoka, Jim Fata, Michael R Johnston
    Abstract:

    We studied the synthetic matrix metalloproteinase inhibitor (MMPI) Prinomastat (AG3340) in a well-established NCI-H460 orthotopic lung cancer model that exhibits highly predictable regional and systemic metastatic patterns. Both primary and metastatic tumors express the matrix metalloproteinases (MMP-2), MT1-MMP (MMP-14) and tissue inhibitor of metalloproteinases (TIMP-2). The anti-tumor activity of Prinomastat was investigated both as a single agent and in combination therapy with carboplatin. Treatment with both carboplatin (at two dose levels) and Prinomastat commenced when the primary lung cancer was approximately 200-300 mg in size and without gross or microscopic evidence of metastases. As single agents, Prinomastat significantly reduced the incidence of kidney metastasis, but had no effect on metastatic frequency to other organs. As single agents neither drug enhanced length of survival over control animals, although microvessel counts in Prinomastat-treated tumors were lower than in tumors from control animals (P<0.01). In combination Prinomastat and the lower dose of carboplatin significantly enhanced survival over control animals, and over animals treated with carboplatin alone (P<0.05). Tolerance to this combination was assessed with body weight and serum biochemistries. At the higher carboplatin dose, toxicity became evident both as a single agent and in combination with Prinomastat. Our results suggest that the administration of Prinomastat in combination with standard cytotoxic chemotherapy during early stages of tumor growth and metastasis may prolong survival in non-small cell lung cancer (NSCLC) patients.

  • ventilator induced lung injury upregulates and activates gelatinases and emmprin attenuation by the synthetic matrix metalloproteinase inhibitor Prinomastat ag3340
    American Journal of Respiratory Cell and Molecular Biology, 2001
    Co-Authors: Hussein D Foda, Krzysztof Appelt, David R Shalinsky, Ellen E Rollo, Michelle Drews, Cathleen Conner, Stanley Zucker
    Abstract:

    Mechanical ventilation has become an indispensable therapeutic modality for patients with respiratory failure. However, a serious potential complication of MV is the newly recognized ventilator-induced acute lung injury. There is strong evidence suggesting that matrix metalloproteinases (MMPs) play an important role in the development of acute lung injury. Another factor to be considered is extracellular matrix metalloproteinase inducer (EMMPRIN). EMMPRIN is responsible for inducing fibroblasts to produce/secrete MMPs. In this report we sought to determine: (1) the role played by MMPs and EMMPRIN in the development of ventilator-induced lung injury (VILI) in an in vivo rat model of high volume ventilation; and (2) whether the synthetic MMP inhibitor Prinomastat (AG3340) could prevent this type of lung injury. We have demonstrated that high volume ventilation caused acute lung injury. This was accompanied by an upregulation of gelatinase A, gelatinase B, MT1-MMP, and EMMPRIN mRNA demonstrated by in situ hybridization. Pretreatment with the MMP inhibitor Prinomastat attenuated the lung injury caused by high volume ventilation. Our results suggest that MMPs play an important role in the development of VILI in rat lungs and that the MMP-inhibitor Prinomastat is effective in attenuating this type of lung injury.

Min H Zhang - One of the best experts on this subject based on the ideXlab platform.

  • phase iii study of matrix metalloproteinase inhibitor Prinomastat in non small cell lung cancer
    Journal of Clinical Oncology, 2005
    Co-Authors: Donald Bissett, Kenneth J Obyrne, J Von Pawel, Ulrich Gatzemeier, Allan Price, Marianne Nicolson, Richard Mercier, Elva Mazabel, Carol Penning, Min H Zhang
    Abstract:

    Purpose Matrix metalloproteinases (MMPs) degrade extracellular proteins and facilitate tumor growth, invasion, metastasis, and angiogenesis. This trial was undertaken to determine the effect of Prinomastat, an inhibitor of selected MMPs, on the survival of patients with advanced non–small-cell lung cancer (NSCLC), when given in combination with gemcitabine-cisplatin chemotherapy. Patients and Methods Chemotherapy-naive patients were randomly assigned to receive Prinomastat 15 mg or placebo twice daily orally continuously, in combination with gemcitabine 1,250 mg/m2 days 1 and 8 plus cisplatin 75 mg/m2 day 1, every 21 days for up to six cycles. The planned sample size was 420 patients. Results Study results at an interim analysis and lack of efficacy in another phase III trial prompted early closure of this study. There were 362 patients randomized (181 on Prinomastat and 181 on placebo). One hundred thirty-four patients had stage IIIB disease with T4 primary tumor, 193 had stage IV disease, and 34 had rec...

  • phase iii study of matrix metalloproteinase inhibitor Prinomastat in non small cell lung cancer
    Faculty of Health; Institute of Health and Biomedical Innovation, 2005
    Co-Authors: Donald Bissett, Kenneth J Obyrne, J Von Pawel, Ulrich Gatzemeier, Allan Price, Marianne Nicolson, Richard Mercier, Elva Mazabel, Carol Penning, Min H Zhang
    Abstract:

    Purpose: Matrix metalloproteinases (MMPs) degrade extracellular proteins and facilitate tumor growth, invasion, metastasis, and angiogenesis. This trial was undertaken to determine the effect of Prinomastat, an inhibitor of selected MMPs, on the survival of patients with advanced non-small-cell lung cancer (NSCLC), when given in combination with gemcitabine-cisplatin chemotherapy. Patients and Methods: Chemotherapy-naive patients were randomly assigned to receive Prinomastat 15 mg or placebo twice daily orally continuously, in combination with gemcitabine 1,250 mg/m2 days 1 and 8 plus cisplatin 75 mg/m2 day 1, every 21 days for up to six cycles. The planned sample size was 420 patients. Results: Study results at an interim analysis and lack of efficacy in another phase III trial prompted early closure of this study. There were 362 patients randomized (181 on Prinomastat and 181 on placebo). One hundred thirty-four patients had stage IIIB disease with T4 primary tumor, 193 had stage IV disease, and 34 had recurrent disease (one enrolled patient was ineligible with stage IIIA disease). Overall response rates for the two treatment arms were similar (27% for Prinomastat v 26% for placebo; P = .81). There was no difference in overall survival or time to progression; for Prinomastat versus placebo patients, the median overall survival times were 11.5 versus 10.8 months (P = .82), 1-year survival rates were 43% v 38% (P = .45), and progression-free survival times were 6.1 v 5.5 months (P = .11), respectively. The toxicities of Prinomastat were arthralgia, stiffness, and joint swelling. Treatment interruption was required in 38% of Prinomastat patients and 12% of placebo patients. Conclusion: Prinomastat does not improve the outcome of chemotherapy in advanced NSCLC. © 2005 by American Society of Clinical Oncology.