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Matrix metalloproteinases
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
S. McDonnell, A. O’Connor, D. Murray, C. C. Lynch
Currendy, a number of MMP inhibitors have been developed and some are in clinical trials as anti-metastatic or anti-cancer therapies. Although many of the initial trials were quite promising, some complications have become apparent in the human trials, with the most severe side-effect being tendonitis in the joints of the shoulders, hands and knees39,40. These results indicate the necessity for further investigation into the normal biological functions of MMPs. Marimastat®, a potent broadspectrum inhibitor of MMPs, proved to be effective in phase I and II trials against colon, ovarian, prostate, lung and pancreatic cancers. Recently, phase III clinical trials involving Marimastat were halted as it was found to be performing worse than the placebo. The bryostatins are a group of naturally occurring macrocyclic lactones which inhibit MMP activity through down-regulation of the protein kinase C pathway. Recently, a number of investigators have begun testing bryostatin compounds for their effectiveness as tumoristatic agents. AG3340/prinostatin has been shown to inhibit the proliferation and invasion of glioma cells in vitro41. In early 2001, phase III clinical trials which were examining the effects of prinostatin on prostate and lung cancers were halted. Phase II trials involving patients with earlier stages of the disease, however, are set to continue.
Early Clinical Trial Design Issues: Patient Populations, End Points, and Barriers
Published in Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo, Lung Cancer, 2016
Normal volunteer studies provide some information relating to PK and safety that may assist in dose/schedule selection; however, these studies alone may not be sufficient to determine recommended doses for phase-2 cancer trials. The degree of toxicity considered “acceptable” or “tolerable” varies between cancer patients and normal volunteers. In addition, PK may be different between healthy volunteers and cancer patients as was seen with MMPI marimastat (9,10). Thus, phase-1 studies in healthy volunteers may precede a phase-1 study in cancer patients that could explore higher doses and dosing of a longer duration, but they are not an alternative for phase-1 study of a new agent in cancer patients as a higher level of toxicity may be considered acceptable and PK may be different.
Imaging Angiogenesis
Published in Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman, Molecular Imaging in Oncology, 2008
Ambros J. Beer, Markus Schwaiger
Inhibition of MMPs activity interferes with both endothelial and tumor cell invasion into the extracellular matrix at primary and metastatic sites. The family of MMPs consists of at least 20 distinct enzymes, of which the gelatinases MMP-2 and MMP-9 are closely associated with angiogenesis. Selective and nonselective MMP inhibitors are in advanced clinical trial. Examples of these agents include marimastat, AG3340 (prinomastat), Col-3, neovastat, and BMS275291. Marimastat demonstrated a survival benefit in patients with metastatic gastric cancer and in patients with glioblastoma treated in combination with temozolomid. However, it is also one of the first antiangiogenic agents, which demonstrated dose-limiting side effects, mostly severe inflammatory polyarthritis (45).
Vascular and extracellular matrix remodeling by physical approaches to improve drug delivery at the tumor site
Published in Expert Opinion on Drug Delivery, 2020
Sara Gouarderes, Anne-Françoise Mingotaud, Patricia Vicendo, Laure Gibot
Matrix remodeling is one of the most valuable approaches to improve the delivery of therapeutic agents as evidenced in vivo with single or chronic injections of pharmacological agents able to degrade tumor ECM proteins. Among them, let’s cite hormones like relaxin [21], enzymes like collagenases [22], angiotensin inhibitor called losartan [23], the antibody simtuzumab to inhibit the lysyl oxidase-like 2 (LOXL2) [24]. Unfortunately, metalloproteinases (MMP) inhibitors (such as marimastat and prinomastat) have not been clinically proven to be effective against cancer, due to their lack of specificity and poor tolerability [25]. One of the flagship studies combining pharmacological ECM matrix remodeling and concomitant treatment with anticancer nanoparticles was published in 2010 by Jain’s team. The authors showed that the repetitive injection of losartan decreased collagen amounts in several mouse tumor models, which in turn favor a higher penetration of doxorubicin-loaded liposomes (Doxil) into the tumor, particularly in the interstitial space, thus improving its therapeutic efficacy [26].
Recent opportunities in matrix metalloproteinase inhibitor drug design for cancer
Published in Expert Opinion on Drug Discovery, 2018
Yue Zhong, Yu-Ting Lu, Ying Sun, Zhi-Hao Shi, Nian-Guang Li, Yu-Ping Tang, Jin-Ao Duan
Over the past 30 years, MMPs have been considered as attractive cancer targets and many different types of synthetic inhibitors have been identified as anticancer drugs [84]. However, only a small number of MMPIs have undergone clinical trials, and several trials were prematurely terminated due to either the lack of benefits or major adverse effects and failed to reach their expectations of increasing survival [85]. For example, Batimastat was the first MMPI entered into clinical trials for the treatment of cancer [86]. In phase I studies, Batimastat was administered to patients with malignant ascites, as well as malignant pleural effusion via direct instillation into the peritoneal and pleural cavities. Batimastat was well tolerated, but short-lasting mild abdominal pain associated with nausea and vomiting was noted in approximately half of the patients; thus, further development of this compound has been suspended. Marimastat, another MMPI, was demonstrated as efficient in phase III trials toward pancreas cancer but failed in breast or lung cancer. Severe musculoskeletal pain was noted in 18% of patients treated with Marimastat, and the quality of life was significantly worse in this group of patients [87].
Challenges with matrix metalloproteinase inhibition and future drug discovery avenues
Published in Expert Opinion on Drug Discovery, 2021
It was observed that the C-terminal fragments showed superior inhibition compared with their N-terminal counterparts, what initialized the development of the first generation hydroxamate-based MMP inhibitors[2,21]. The most famous representatives of this pioneering substrate-related derivatives are marimastat 3Figure 3, batimastat 4Figure 3 and ilomastat 5Figure 3, which were already capable of inhibiting MMPs with nanomolar or even sub-nanomolar IC50 values. Marimastat 3Figure 3 as well as batimastat 4Figure 3 advanced to clinical trials, where both failed. Batimastat 4Figure 3 was examined for its effectiveness in treatment of malignant pleural effusions and advanced to phase III trials where it exhibited poor oral bioavailability and peritonitis as a side effect what led to termination of the trials[73,74]. In contrast, marimastat 3Figure 3 was orally available and it advanced to phase III clinical trials in patients suffering from metastatic breast cancer[75]. Nevertheless, it failed the trials due to a lack of therapeutic effect as well as side effects like musculoskeletal toxicity (MST), and patients treated with it suffered from reduced survival[75]. In addition, marimastat 3Figure 3 caused musculoskeletal syndrome (MSS), or tendinitis, in rats[76] what was postulated to be caused by the simultaneous inhibition of MMP-1[77–79] and MMP-14[80,81]. Therefore, further research aimed at developing MMP inhibitors that spared MMP-1. Structural analysis of MMP-1 revealed a rather shallow S1ʹ channel compared with MMP-8 or MMP-13 for example, providing the basis for inhibitors with initial selectivity[82,83].