Randomized Phase II Trial of Matrix Metalloproteinase Inhibitor COL-3 in AIDS-Related Kaposi's Sarcoma: An AIDS Malignancy Consortium Study

Dezube, Bruce J.; Krown, Susan E.; Lee, Jeannette; Bauer, Kenneth S.; Aboulafia, David M.

doi:10.1200/jco.2005.04.2614

Cited by 152 publications

(92 citation statements)

References 24 publications

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“…Unlike many agents recently investigated as potential KS treatments (e.g., the MMP inhibitor COL-3 [73], rapamycin [24] and imatinib [23]), which are purported to narrowly target proteins and signaling pathways that are over-expressed or activated in KS and are subject to focused analysis using serial sampling of blood or tumor tissue during the course of clinical trials, the multiplicity of IFN's potential mechanisms of action in KS is daunting. Most of the relatively large clinical trials of IFNα in KS were conducted well before the introduction of HAART, the discovery and characterization of KSHV, the elucidation of IFN's many potentially relevant activities and the technical capacity to study these as part of clinical trials.…”

Section: Multiple Potential Mechanisms Of Actionmentioning

confidence: 99%

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

Krown

2007

Cytokine & Growth Factor Reviews

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Interferon alfa (IFNA) was one of the first agents to be used therapeutically in AIDS-associated Kaposi's sarcoma (KS) more than 25 years ago, and induces tumor regression in a subset of patients. Although much has been learned about the clinical role of IFNα in KS treatment, little is currently known about the mechanism(s) by which IFNA causes KS regression. This is despite a growing understanding of both KS pathogenesis and relevant IFNA activities. To a large extent other agents have supplanted IFNA as treatments for KS, but there may still remain a therapeutic role for IFNA, possibly in combination with other agents targeting angiogenesis and/or HHV-8-encoded human gene homologs that encode proteins involved in cell cycle regulation and signaling. KeywordsInterferon; Kaposi's sarcoma In 1995, when I was honored as a recipient of the ISICR Milstein Award, the AIDS epidemic had recently begun its 15 th year and the human immunodeficiency virus (HIV-1) had been isolated some 12 years previously [1]. However, the virus associated with Kaposi's sarcoma (KS), the most common AIDS-associated malignancy, had been described less than a year earlier [2], its significance was still in some question and its role in KS development had not been characterized, and the active combination drug regimens with which we now treat HIV infection had not yet become widely available. Recombinant interferon alfa preparations (IFNα2a and IFNα2b), which had received approval from the U.S. Food and Drug Administration (FDA) for treatment of AIDS-associated KS in 1988, were still the only approved drugs for systemic treatment of KS (the chemotherapeutic agent, liposomal doxorubicin, would receive FDA approval later in 1995, as did liposomal daunorubicin in 1996 and paclitaxel in 1997). Now, more than a quarter century after the first published reports describing AIDS and its association with KS [3-6] and our first modestly successful attempts to treat KS with IFNα [7], this agent is used infrequently to treat KS, although it still finds use in HIV-infected individuals co-infected with hepatitis C. In this brief review, I will summarize some of the history of IFNα in the treatment of AIDS-associated KS, concentrating on examples of clinical trials in which I have personally been involved, and consider whether there remains a potentially valuable role for this agent in KS treatment.

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Section: Multiple Potential Mechanisms Of Actionmentioning

confidence: 99%

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

Krown

2007

Cytokine & Growth Factor Reviews

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“…In vitro studies showed that the 'C' to 'T' substitution at À1562 position results in the loss of binding of a nuclear repressor protein, thus leading to increased MMP-9 expression. 23 The g.À90(CA)14-24 polymorphism, however, caused a 50% reduction in MMP-9 promoter activity when the (CA) 14 allele was compared with the (CA) 21 allele. 24 These polymorphisms have been associated with cardiovascular diseases.…”

Section: Introductionmentioning

confidence: 96%

“…[17][18][19][20][21] Therefore, it is possible that the circulating levels of MMP-9 reflect the increased susceptibility to cardiovascular diseases in HIV patients.…”

Section: Introductionmentioning

confidence: 99%

A genetic polymorphism of matrix metalloproteinase 9 (MMP-9) affects the changes in circulating MMP-9 levels induced by highly active antiretroviral therapy in HIV patients

et al. 2009

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We examined whether two functional polymorphisms (g.À1562C4T and g.À90(CA)14-24) in the matrix metalloproteinase (MMP)-9 gene or MMP-9 haplotypes affect the circulating levels of pro-MMP-9 and pro-MMP-9/TIMP-1 (tissue inhibitor of metalloproteinase-1) ratios in AIDS patients, and modulate alterations in these biomarkers after highly active antiretroviral therapy (HAART). We studied 82 patients commencing HAART. Higher pro-MMP-9 concentrations and pro-MMP-9/TIMP-1 ratios were found in CT/TT patients compared with CC patients. HAART decreased pro-MMP-9 levels and pro-MMP-9/TIMP-1 ratios in CT/TT patients, it did not modify pro-MMP-9 levels and it increased pro-MMP-9/TIMP-1 ratios in CC patients. The g.À90(CA)14-24 polymorphism, however, produced no significant effects. Moreover, we found no significant differences in HAARTinduced changes in plasma pro-MMP-9, TIMP-1 and pro-MMP-9/TIMP-1 ratios when different MMP-9 haplotypes were compared. These findings suggest that the g.À1562C4T polymorphism affects pro-MMP-9 levels in patients with AIDS and modulates the alterations in pro-MMP-9 levels caused by HAART, thus possibly affecting the risk of cardiovascular complications.

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“…Matrix metalloproteinase (MMPs) are highly expressed in KS lesions and may contribute to angiogenesis via degradation of the extracellular matrix. A phase II study of the MMPs inhibitor demonstrated a 41% overal response rate [77]. Activation of c-kit and platelet-derived growth factor receptor (PDGFR) have effects on angiogenesis and growth of KS cells.…”

Section: Electrochemotherapymentioning

confidence: 99%

Kaposi’s Sarcoma Epidemiology, Risk Factors, Staging and Treatment: AN OVERVIEW.

Karakaş¹,

Aksoy²,

Gullu³

2017

Acta Oncol Tur.

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ÖZETKaposi sarkomu immun disfonksiyon ve muhtemel viral etiyolojiye bağlı oluşan anjioproliferatif bir hastalıktır. Kaposi sarkomu etiyolojilerine göre 4 alt tipe ayrılır. Hastalığın tedavi seçenekleri ve klinik seyri açısından alt tipler bizlere fikir verir. Ülkemizde ve dünyada nadir görülen bir hastalık olması nedeniyle şu an için randomize kontrollü çalışmaları bulunmamaktadır. Kaposi sarkomundaki bilgilerimiz genelde retrospektif ve faz II çalışmalara dayanmaktadır. Bu derlememiz kaposi sarkomunun epidemiyolojisi, risk faktörleri ve son tedavi stratejileriini içermektedir. Anahtar Kelimeler: Kaposi sarkomu, risk faktörleri, tedavi ABSTRACT Kaposi's sarcoma (KS) is an angioproliferative disease, with a viral etiology and a multifactorial pathogenesis that depends on an immune dysfunction. It is divided into four types according to the aetiology. There was no randomized controlled trials due to very rare disease. Thus clinical guidelines has not been established properly. This review summarized epidemiology, risk factor, and recent treatment strategies in Kaposi sarcoma patients.

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Randomized Phase II Trial of Matrix Metalloproteinase Inhibitor COL-3 in AIDS-Related Kaposi's Sarcoma: An AIDS Malignancy Consortium Study

Abstract: COL-3, when administered as 50 mg/d, is both active and well tolerated in the treatment of AIDS-related KS. COL-3 is a promising agent for the treatment of this opportunistic neoplasm of AIDS.

Cited by 152 publications

References 24 publications

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

A genetic polymorphism of matrix metalloproteinase 9 (MMP-9) affects the changes in circulating MMP-9 levels induced by highly active antiretroviral therapy in HIV patients

Kaposi’s Sarcoma Epidemiology, Risk Factors, Staging and Treatment: AN OVERVIEW.

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