Active Ingredients: Doxycycline
At present, inhibition of the function of MMPs in the extracellular matrix is being most actively pursued for anticancer therapy. Theoretically, the ability of TIMPs to potently and specifically inhibit the activity of several MMPs could result in a beneficial therapeutic effect 83.
However, the lack of effective methods of systemic gene delivery has limited the clinical utility of this approach, whereas the development of synthetic inhibitors of MMPs has been actively pursued and widely tested in clinical trials Table 2 5 — 7.
Inhibitors of MMPs fall into three pharmacologic categories: 1 collagen peptidomimetics and nonpeptidomimetics, 2 tetracycline derivatives, and 3 bisphosphonates.Published by Baishideng Publishing Group Inc. Haifa 34362, Israel.
Peptidomimetic MMP Inhibitors These compounds are pseudopeptide derivatives that have been synthesized to mimic the structure of collagen at the site where MMP binds to cleave it. The inhibitor binds reversibly at the active site of the MMP in a stereospecific manner and chelates the zinc atom on the enzyme activation site 86.
Several zinc-binding groups have been tested for their ability to competitively inhibit MMP by binding at the active site; these groups include carboxylates, aminocarboxylates, sulfhydryls, derivatives of phosphoric acid, and hydroxamates.
Most MMP inhibitors in clinical development are hydroxamate derivatives.
Batimastat, the first MMP inhibitor evaluated in cancer patients, is a nonorally bioavailable low-molecular-weight hydroxamate. In vitro, batimastat had cytostatic effects against a variety of cancer cell lines and was not cytotoxic 7.
Batimastat also induced significant antiproliferative effects in several preclinical models of cancer, including inhibition of tumor growth in orthotopic tumor xenografts model, inhibition of metastasis in experimental metastasis models, and suppression of ascites formation in ovarian cancer models 87 — 96.
Early-stage tumors were more sensitive to batimastat than tumors at later stages of development. The drug also potentiated the growth-suppressive activity of cisplatin and demonstrated synergistic antitumor effects with docetaxel and captopril 97.
Table 3 summarizes the principal results from clinical trials with this agent. Systemic toxicity has been mild and of no clinical consequences. Batimastat treatment also resulted in beneficial effects in the majority of patients with pleural effusion who were treated with the drug, as measured by dyspnea scores and a reduction in the requirement for thoracentesis 100.
The drug contains a collagen-mimicking hydroxamate structure that chelates the zinc ion at the active site of MMPs. Preclinical studies 6 of marimastat against lung and breast cancer experimental metastases models demonstrated a reduction in the number and size of metastatic foci in treated versus control animals.
Doxycycline effect on collagen synthesis In order to determine whether collagen synthesis is affected in the presence of doxycycline 20 nM, we assessed the proline incorporation into proteins sensitive to collagenase hydrolysis.