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.
"For example, chemical conversion of tetracycline hydrochloride to the analog with no antimicrobial activity, de-dimethylaminotetracycline, has not compromised the collagenase inhibitory activity of the original molecule (Golub et al., 1987), while not affecting the tetracycline resistance profiles of gut and oral microbiota (Golub et al., 1991). COL-3, a chemically modified tetracycline with a MMP inhibitor activity, has showed promising results in the treatment of AIDS-related Kaposi’s sarcoma (Dezube et al., 2006). Moreover, the use of modified tetracyclines has showed promising results in many fields, including ophthalmologic diseases (Federici, 2011), dentistry (Grenier et al., 2002; Gu et al., 2012), cardiovascular pathologies (Salo et al., 2006; Gu et al., 2011), various types of cancer (Lokeshwar, 1999, 2011; Syed et al., 2004; Zhao et al., 2013a), and other conditions with excessive MMPs activities (Golub, 2011). "
[Show abstract][Hide abstract] ABSTRACT: Biological functions of antibiotics are not limited to killing. The most likely function of antibiotics in natural microbial ecosystems is signaling. Does this signaling function of antibiotics also extend to the eukaryotic - in particular mammalian - cells? In this review, the host modulating properties of three classes of antibiotics (macrolides, tetracyclines, and β-lactams) will be briefly discussed. Antibiotics can be effective in treatment of a broad spectrum of diseases and pathological conditions other than those of infectious etiology and, in this capacity, may find widespread applications beyond the intended antimicrobial use. This use, however, should not compromise the primary function antibiotics are used for. The biological background for this inter-kingdom signaling is also discussed.
Frontiers in Microbiology 08/2013; 4:241. DOI:10.3389/fmicb.2013.00241 · 3.99 Impact Factor
"As a result of the discovery of the active site for at least many of the pleiotropic mechanisms by which TCs inhibit collagenolysis, the second strategy of the group was to chemically modify the TC molecule to eliminate its antibiotic activity (by removal of the dimethylamino group at carbon-4 of the ‘A’ ring (16)) but to retain its zinc-binding β-diketone site (see above) to preserve, or even enhance, its anti-collagenase activity (11, 14, 16). As a result, an initial series of chemically modified TCs, CMTs 1–10 (14), were developed and one of the most potent MMP inhibitors of this series, CMT-3 (6-demethyl 6-deoxy 4-de-dimethylamino TC; also known as COL-3), has been tested in phase II clinical trials by Dezube et al. (21), through a cooperative research and development agreement (CRADA) with the National Cancer Institute (NCI), on patients with Kaposi's sarcoma, and has shown efficacy as an anti-angiogenesis agent (21, 22). The same compound, CMT-3, significantly reduced mortality in a Yorkshire pig model and other animal models of a 40% fatal lung disease, acute respiratory distress syndrome (ARDS) and counteracts septic shock (23–26). "
[Show abstract][Hide abstract] ABSTRACT: In 1983, it was first reported that tetracyclines (TCs) can modulate the host response, including (but not limited to) inhibition of pathologic matrix metalloproteinase (MMP) activity, and by mechanisms unrelated to the antibacterial properties of these drugs. Soon thereafter, strategies were developed to generate non-antibacterial formulations (subantimicrobial-dose doxycycline; SDD) and compositions (chemically modified tetracyclines; CMTs) of TCs as host-modulating drugs to treat periodontal and other inflammatory diseases. This review focuses on the history and rationale for the development of: (a) SDD which led to two government-approved medications, one for periodontitis and the other for acne/rosacea and (b) CMTs, which led to the identification of the active site of the drugs responsible for MMP inhibition and to studies demonstrating evidence of efficacy of the most potent of these, CMT-3, as an anti-angiogenesis agent in patients with the cancer, Kaposi's sarcoma, and as a potential treatment for a fatal lung disease (acute respiratory distress syndrome; ARDS). In addition, this review discusses a number of clinical studies, some up to 2 years' duration, demonstrating evidence of safety and efficacy of SDD formulations in humans with oral inflammatory diseases (periodontitis, pemphigoid) as well as medical diseases, including rheumatoid arthritis, post-menopausal osteopenia, type II diabetes, cardiovascular diseases, and a rare and fatal lung disease, lymphangioleiomyomatosis.
Journal of Oral Microbiology 10/2012; 4(2012). DOI:10.3402/jom.v4i0.19227
"A concern about the CMTs as potential therapeutic agents, with greater efficacy than SDD, is the side-effect of photosensitivity, already seen in clinical trials testing CMT-3. A significant incidence of sunburn has been seen in humans administered relatively high oral doses, 50-150 mg/day  . In contrast, in a preliminary study on subjects administered a much lower oral dose of CMT-3, 10 mg/day, this phenomenon was not observed, yet the data indicated a reduction in biomarkers of collagen degradation and bone resorption (MMP-8 and IL-1β levels) in the GCF of lesions (pockets) in patients with periodontitis . "
[Show abstract][Hide abstract] ABSTRACT: Periodontitis (progressive inflammatory disease characterized by alveolar bone loss, a major cause of tooth loss worldwide) is associated with both systemic osteoporosis and its milder form, osteopenia. Tetracyclines, by virtue of their non-antimicrobial pro-anabolic and anti-catabolic properties, are excellent candidate pharmaceuticals to simultaneously treat these local and systemic disorders. This paper reviews the foundational basic science and translational research which lead to a pivotal multicenter randomized clinical trial in postmenopausal women with both periodontitis and systemic (skeletal) osteopenia. This trial was designed primarily to examine whether subantimicrobial dose doxycycline (SDD) could reduce progressive alveolar (oral) bone loss associated with periodontitis and, secondarily, whether SDD could reduce systemic bone loss in the same subjects. This paper describes the efficacy and safety findings from this clinical trial and also outlines future directions using this promising and novel approach to manage both oral and systemic bone loss.
Pharmacological Research 10/2010; 63(2):121-9. DOI:10.1016/j.phrs.2010.10.006 · 4.41 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.