Randomized phase II trial of matrix metalloproteinase inhibitor COL-3 in AIDS-related Kaposi's sarcoma: An AIDS Malignancy Consortium study
ABSTRACT Matrix metalloproteinases (MMPs) are involved in tumor metastasis and are overexpressed in Kaposi's sarcoma (KS) cells. In a phase I trial of the MMP inhibitor COL-3 in patients with AIDS-related KS, the drug was well tolerated, KS regression was observed, and MMP-2 levels decreased significantly in responders compared with nonresponders. The aim of this trial was to extend these initial observations.
This was a randomized, parallel-group, phase II study. COL-3 was administered orally once daily at one of two doses (group A received 50 mg and group B received 100 mg) to patients with AIDS-related KS. Antiretroviral therapy was permitted but not required. Serial tumor assessments and plasma levels of MMPs were obtained. Study end points were progressive KS and recurrent dose-limiting toxicity.
Seventy-five patients received COL-3: 37 in group A and 38 in group B. Fifty-seven patients (76%) had received prior KS therapy. Thirty-three patients (44%) had more than 50 KS lesions. The response rate in group A was 41%, which was significantly greater than the prespecified target rate of 20% (95% CI, 25% to 58%; P = .003); the response rate of group B was 29% (P = not significant). There were significant declines in MMP-2 and MMP-9 plasma levels from baseline to minimum value with treatment (MMP-2, P < .001; MMP-9, P = .001). The most common adverse events were photosensitivity and rash.
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.
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ABSTRACT: HIV infection is related to an increased risk of cancer compared with general population, both AIDS-defining cancers (Kaposi's sarcoma, non Hodgkin's lymphoma, invasive cervical cancer) and non-AIDS-defining cancers. Although the advent of the highly active antiretroviral therapy era has decreased the Kaposi's sarcoma and non-Hodgkin's lymphoma incidences, non-AIDS-defining malignancies, such as lung cancer, hepatocarcinoma, anal cancer and skin cancers, remain a major cause of morbidity and death in the HIV-infected population. The clinical presentation is often different between the infected and non-infected populations, often with a more advanced stage at diagnosis, a more aggressive pathology, and associated morbidities like immunosuppression, leading to poorer outcomes. Numerous studies have focused on HIV-related malignancies' treatment, however specific guidelines are still missing. Practitioners have to be careful with interactions between antiretroviral and antineoplastic drugs, particularly through the cytochrome P 450. Because of this, a national multidisciplinary approach, "Cancer and HIV, " was started in 2013 thanks to the National Institute of Cancer (INCa). The aim of this review is to present a scientific update about AIDS-and non-AIDS-defining malignancies, both in their clinical aspects and regarding their specific therapeutic management.Bulletin du cancer 11/2014; 101(11):1020-1029. DOI:10.1684/bdc.2014.2032 · 0.64 Impact Factor
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ABSTRACT: Antimicrobial agents are undoubtedly one of the key advances in the history of modern medicine and infectious diseases, improving the clinical outcomes of infection owing to their inhibitory effects on microbial growth. However, many antimicrobial agents also have biological activities stemming from their interactions with host receptors and effects on host inflammatory responses and other human or bacterial cellular biological pathways. These result in clinical uses of antimicrobial drugs that are distinct from their direct bacteriostatic or bactericidal properties. We reviewed the published literature regarding non–anti-infective therapeutic properties and proposed clinical applications of selected antimicrobials, specifically, macrolides, tetracyclines, sulfonamides, and ketoconazole. The clinical applications reviewed were varied, and we focused on uses that were clinically relevant (in terms of importance and burden of disease) and where published evidence exists. Such uses include chronic inflammatory pulmonary and skin disorders, chronic periodontitis, gastrointestinal dysmotility, rheumatoid arthritis, and cancer. Most of these potential therapeutic uses are not Food and Drug Administration approved. Clinicians need to weigh the use of antimicrobial agents for their non–anti-infective benefits, considering potential adverse effects and long-term effect on microbial resistance.Mayo Clinic Proceedings 11/2014; 90(1). DOI:10.1016/j.mayocp.2014.09.006 · 5.81 Impact Factor
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ABSTRACT: Tetracycline analogues (TCNAs) have been shown to inhibit matrix metalloproteinases and to induce apoptosis in several cancer cell types. In the present study, the cytotoxic effects of TCNAs doxycycline (DOXY), minocycline (MINO) and chemically modified tetracycline-3 (COL-3) were investigated in the human acute myeloid leukemia HL-60 cell line. Cells were incubated with TCNAs in final concentrations of 0.5-100 µg/ml for 24 h. Viability of the leukemic cells was inhibited in a concentration-dependent manner using resazurin assay. The estimated IC50s were 9.2 µg/ml for DOXY, 9.9 µg/ml for MINO and 1.3 µg/ml for COL-3. All three TCNAs induced potent cytotoxic effects and cell death. Apoptosis, which was assessed by morphological changes and annexin V positivity, was concentration- and time-dependent following incubation with any one of the drugs. TCNAs induced DNA double strand breaks soon after treatment commenced as detected by γH2AX and western blot. The loss of mitochondrial membrane potential (Δψm), caspase activation and cleavage of PARP and Bcl-2 were observed; however, the sequence of events differed among the drugs. Pancaspase inhibitor Z-VAD-FMK improved survival of TCNAs-treated cells and decreased TCNAs-induced apoptosis. In summary, we demonstrated that TCNAs had a cytotoxic effect on the HL-60 leukemic cell line. Apoptosis was induced via mitochondria-mediated and caspase-dependent pathways in HL-60 cells by all three TCNAs. COL-3 exerted the strongest anti-proliferative and pro-apoptotic effects in concentrations that have been achieved in human plasma in reported clinical trials. These results indicate that there is a therapeutic potential of TCNAs in leukemia.PLoS ONE 12/2014; 9(12):e114457. DOI:10.1371/journal.pone.0114457 · 3.53 Impact Factor