Randomized Phase III Trial of Marimastat Versus Placebo in Patients With Metastatic Breast Cancer Who Have Responding or Stable Disease After First-Line Chemotherapy: Eastern Cooperative Oncology Group Trial E2196

Sparano, Joseph A.; Bernardo, Patricia; Stephenson, Patricia; Gradishar, William J.; Ingle, James N.; Zucker, Stanley; Davidson, Nancy E.

doi:10.1200/jco.2004.08.054

Cited by 226 publications

(154 citation statements)

References 41 publications

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“…These concentrations are, respectively, 1,000-fold and 100-fold higher than the in vitro IC 50 of ALS 1-0635 against MMP-13. Plasma Marimastat concentrations (trough) of 10 ng/ml are known to induce MSS in humans (38). Considering that the IC 50 of Marimastat against MMP-13 is 4.59 nM, the margin between potency and toxicity is only ϳ2-fold.…”

Section: Discussionmentioning

confidence: 99%

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

Baragi

Becher²,

Bendele³

et al. 2009

Arthritis & Rheumatism

151

127

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Objective. Matrix metalloproteinases (MMPs) have long been considered excellent targets for osteoarthritis (OA) treatment. However, clinical utility of broad-spectrum MMP inhibitors developed for this purpose has been restricted by dose-limiting musculoskeletal side effects observed in humans. This study was undertaken to identify a new class of potent and selective MMP-13 inhibitors that would provide histologic and clinical efficacy without musculoskeletal toxicity.Methods. Selectivity assays were developed using catalytic domains of human MMPs. Freshly isolated bovine articular cartilage or human OA cartilage was used in in vitro cartilage degradation assays. The rat model of monoiodoacetate (MIA)-induced OA was implemented for assessing the effects of MMP-13 inhibitors on cartilage degradation and joint pain. The surgical medial meniscus tear model in rats was used to evaluate the chondroprotective ability of MMP-13 inhibitors in a chronic disease model of OA. The rat model of musculoskeletal side effects (MSS) was used to assess whether selective MMP-13 inhibitors have the joint toxicity associated with broad-spectrum MMP inhibitors.Results. A number of non-hydroxamic acidcontaining compounds that showed a high degree of potency for MMP-13 and selectivity against other MMPs were designed and synthesized. Steady-state kinetics experiments and Lineweaver-Burk plot analysis of rate versus substrate concentration with one such compound, ALS 1-0635, indicated linear, noncompeti-

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Section: Discussionmentioning

confidence: 99%

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

Baragi

Becher²,

Bendele³

et al. 2009

Arthritis & Rheumatism

151

127

View full text Add to dashboard Cite

show abstract

“…Despite impressive preclinical anticancer activity [28][29][30][31][32] and the suggestion of biological activity in phase I and phase II trials, 33,34 the MMPIs as a single agent or in combination with chemotherapeutic agent have been disappointing thus far in randomized clinical trials for solid tumors. 35,36 However, given the role of MMPIs in colorectal tumorigenesis, the synthetic MMPIs could find an even more important role in primary and/or secondary colorectal cancer prevention than in the treatment of established disease. Given their cytostatic mechanisms of action, MMPIs might also prove most beneficial at reducing recurrence rates in individuals who have undergone potentially curative resections, and MMPIs should be tested in adjuvant therapy programs in this population.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of the MMP inhibitor MMI270 against lung metastasis following removal of orthotopically transplanted human colon cancer in rat

Osuga

Matono

Nakajima

et al. 2005

Intl Journal of Cancer

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We have investigated the antitumor effects of synthetic MMP inhibitor MMI270 against postoperative lung metastasis from colon cancer in nude rat. The KM12SM human colon cancer cells were injected into the cecal wall, and at 5 weeks after the injection, the cecum was removed including the tumor. Then, 30 mg/kg of MMI270 was administered perorally twice per day for 2 or 4 weeks, either immediately after removal or after week 2 after the removal. At week 7 after the removal, lung metastasis was significantly inhibited by the early administration of MMI270 immediately after the tumor removal but not by the late administration. The survival rates were significantly higher in the rats treated by early administration of MMI270 compared to the survival rate in untreated rats. Moreover, no lung metastasis was detected in some rats with 24-weeks' survival treated by early administration. Lower microvessel density, lower PCNA Index and higher Apoptotic Index in the lung metastases of the rats treated with MMI270 were found compared to those in untreated rats. A beneficial effect of by early administration of MMI270 against postoperative lung metastases may be expected through inhibiting neovascularization of metastases in nude rat. ' 2005 Wiley-Liss, Inc.Key words: preclinical lung metastases model; angiogenesis; apoptosis; postoperative adjuvant therapy Colorectal cancer remains one of the major causes of cancer death worldwide. The mainstay of treatment for colorectal cancer with curative intent is surgical resection. However, recurrences to the liver or lung may occur in some patients even after a potentially curative operation. 1 For instance, the overall 5-year-survival rate for stage III cancer is approximately 60 % 2 due to postoperative recurrences even if the patients receive adjuvant chemotherapy. It is thought that the development of distant metastases depends on the spread of cancer cells from the primary tumor and that micrometastases already established prior to primary tumor resection appear as recurrent tumors after the operation. Therefore, to improve the postoperative prognosis of patients with colorectal cancer, effective adjuvant therapies against the micrometastases such as chemotherapy and immunotherapy should be considered. Since the 1990s, chemotherapy using 5-fluorouracil and leucovorin (5-FU/LV) has become standard treatment for stage III colon cancer after successful surgery. 3,4 However, this chemotherapy is still insufficient for patients at a high risk to recurrence who have biologically aggressive tumors, and the need to improve the outcome in such patients has increased the interest in developing more intensive or more targeted therapeutic strategies.It has been shown that solid tumor growth beyond a certain size requires neovascularization to supply the tumor with oxygen and nutrients. 5 In other words, without neovascularization, micrometastasis cannot grow. Therefore, it has been suggested that antiangiogenic therapy is effective against various solid tumors by inhibiting neovascularizat...

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“…No significant benefit in survival or disease progression was found in patients with advanced-stage pancreatic, gastric, breast, non-small cell lung, and prostate cancer. [68][69][70] Some clinical trials have had promising results in gastric cancer and nonsmall cell lung cancer. 71,72 Patients with limited musculoskeletal symptoms have had improved survival in recent studies.…”

Section: Matrix Metalloprotease Inhibitors In Clinical Trialsmentioning

confidence: 99%

“…71,72 Patients with limited musculoskeletal symptoms have had improved survival in recent studies. 68 A clinical trial of MMP inhibitors in head and neck cancer has not been published, but reports in other cancers imply that broad-spectrum inhibitors will have limited clinical benefit (Table 2) because of dose-limiting musculoskeletal symptoms. Addition of MPIs to conventional platinum-based cytotoxic agents is well tolerated by patients, suggesting the potential for combination therapy.…”

Section: Matrix Metalloprotease Inhibitors In Clinical Trialsmentioning

confidence: 99%

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Matrix metalloproteases in head and neck cancer

Rosenthal¹,

2006

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Matrix metalloproteases (MMPs) are a collection of enzymes capable of cleaving extracellular matrix components, growth factors, and cell-surface receptors. MMPs modulate most aspects of tumorigenesis and are highly expressed in cancer compared with normal tissues. Preclinical studies have demonstrated that head and neck squamous cell carcinomas (HNSCCs) express high levels of MMPs in vivo and that inhibition of these enzymes in vitro and in mouse models decreases invasion and metastasis. However, the clinical trials for MMP inhibitors have failed to demonstrate a significant survival advantage in most cancers. The disparity between preclinical and clinical studies has led to the reevaluation of how MMP functions in cancer and the design of clinical trials for molecularly targeted agents. Mouse model data and analysis of HNSCC tumor specimens suggests that membrane type-1 MMP (MT1-MMP) may be a critical enzyme in tumor cell invasion and survival in vivo. This accumulated data provide evidence for development of selective MT1-MMP inhibitors as therapy in HNSCC.Keywords matrix metalloprotease inhibitor; MMP; extracellular matrix; head and neck cancer; squamous cell carcinoma; membrane type-1 MMP; drug development; proteases The hallmark of cancer remains regional and distant metastases. Regional metastasis in head and neck squamous cell carcinoma (HNSCC) decreases survival by almost 50%, and invasion beyond the lymph node capsule further decreases survival. 1 For tumor cells to invade and metastasize they must: (1) develop motility, (2) alter cell-cell and cell-matrix adhesion, and (3) remodel the extracellular matrix. 2 It was recognized in the 1980s that matrix metalloprotease (MMP) could degrade extracellular matrix (ECM) components and that this could potentiate local tumor invasion and metastasis. 3 A significant amount of effort has been funneled into the development of MMP inhibitors (MPIs) promote tumor angiogenesis by mobilizing or activating factors such as basic fibroblast growth factor, vascular endothelial growth factor, or transforming growth factor-beta. 15,16,18 Second, the complexity of cell types expressing MMPs in the tumor mass was appreciated ( Figure 1 ASSESSMENT OF MATRIX METALLOPROTEASES IN HEAD AND NECK CANCERMMPs consistently found overexpressed in head and neck cancer include MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-13, and MMP-14 (Table 1). However, MMP-1, MMP-2, MMP-9, and MT-1 MMP are most commonly identified in HNSCC and associated with disease progression. With the understanding that conflicting reports are abundant and negative studies unlikely to be published, it is possible to summarize the extensive MMP findings in HNSCC. Although most studies evaluate only one or two MMPs within a given head and neck site, studies have examined expression of multiple TIMPs and MMPs in oral cavity SCC. 12,22 Interestingly, these studies commonly identify upregulation of TIMP-1, which is associated with a poor survival. Levels of TIMP-2 are often unchanged between t...

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Randomized Phase III Trial of Marimastat Versus Placebo in Patients With Metastatic Breast Cancer Who Have Responding or Stable Disease After First-Line Chemotherapy: Eastern Cooperative Oncology Group Trial E2196

Abstract: Marimastat does not prolong PFS when used after first-line chemotherapy for metastatic breast cancer. Patients with higher marimastat levels exhibited MST, and MST was associated with inferior survival.

Cited by 226 publications

References 41 publications

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

Efficacy of the MMP inhibitor MMI270 against lung metastasis following removal of orthotopically transplanted human colon cancer in rat

Matrix metalloproteases in head and neck cancer

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