Drugs online research references
Anticancer Res. 1993 Nov-Dec;13(6A):2101-6.
Response of the FSaII fibrosarcoma to antiangiogenic modulators plus cytotoxic agents.
Teicher BA, Holden SA, Ara G, Northey D.
Dana-Farber Cancer Institute, Boston, MA 02115.
The formation of a blood supply (angiogenesis) is critical to the growth of solid tumors. The naturally occurring steroid tetrahydrocortisol, the synthetic cyclodextrin derivative beta-cyclodextrin tetradecasulfate, and the tetracycline derivative minocycline have antiangiogenic activity. Tetrahydrocortisol (125 mg/kg) and beta-cyclodextrin tetradecasulfate (1000 mg/kg) in a 1:1 molar ratio by continuous infusion over 14 days and minocycline (10 mg/kg) administered i.p. daily from day 4 to day 18 postimplantation of the FSaII fibrosarcoma did not alter the growth of the tumor. These antiangiogenic modulators were not cytotoxic toward FSaIIC tumor cells or bone marrow CFU-GM when tumor-bearing animals were treated and cytotoxicity determined by colony formation in culture. The antiangiogenic modulators markedly increased the cytotoxicity of cyclophosphamide toward FSaIIC tumor cells and to a much lesser degree toward bone marrow CFU-GM. The cytotoxicity of CDDP and radiation was enhanced only by administration of the three modulators in combination. In tumor growth delay studies, the three modulator combination increased the effectiveness of CDDP by 1.5-fold, of cyclophosphamide by 1.9-fold and of radiation by 1.4-fold. Although the antiangiogenic therapies alone did not substantially reduce the number of lung metastases compared with the untreated controls, addition of the antiangiogenic agents to treatment with the cytotoxic therapies reduced not only the number of lung metastases formed from the primary tumor but also reduced the number of large metastases. Thus, antiangiogenic therapies can potentiate the efficacy of standard anticancer therapies.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7507654&dopt=Abstract
Int J Cancer. 1994 Jun 15;57(6):920-5.
Potentiation of cytotoxic cancer therapies by TNP-470 alone and with other anti-angiogenic agents.
Teicher BA, Holden SA, Ara G, Sotomayor EA, Huang ZD, Chen YN, Brem H.
Dana-Farber Cancer Institute, Boston, MA.
The ability of TNP-470, a synthetic analog of fumagillin which has been described as an anti-angiogenic agent, to potentiate cytotoxic cancer therapies was investigated in vivo in the murine FSaIIC fibrosarcoma and the Lewis lung carcinoma. TNP-470 was more toxic toward FSaIIC tumor cells from tumors treated in vivo than toward bone-marrow CFU-GM from the same animals. TNP-470 had a dose-modifying effect on the toxicity of cyclophosphamide toward FSaIIC tumor cells which amounted to an 8-fold increase in tumor-cell killing at a cyclophosphamide dose of 500 mg/kg. Treatment with TNP-470 and minocycline increased the permeability of the FSaII fibrosarcoma in vivo to the fluorescent dye Hoechst 33342 and increased the killing of both the bright and the dim tumor cells by cyclophosphamide. TNP-470, especially in combination with minocycline, formed a highly effective modulator combination for treatment of the Lewis lung carcinoma with cytotoxic cancer therapies against primary and metastatic disease. The combination of TNP-470/minocycline and cyclophosphamide led to 40 to 50% long-term survivors in Lewis-lung-carcinoma-bearing animals. Our results indicate that the use of anti-angiogenic modulators in cancer therapy is a very promising area for further study.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7515861&dopt=Abstract
Cancer Chemother Pharmacol. 1995;36(5):418-24.
The tetracycline analogs minocycline and doxycycline inhibit angiogenesis in vitro by a non-metalloproteinase-dependent mechanism.
Gilbertson-Beadling S, Powers EA, Stamp-Cole M, Scott PS, Wallace TL, Copeland J, Petzold G, Mitchell M, Ledbetter S, Poorman R.
Cancer and Infectious Diseases Research, Upjohn Laboratories, Upjohn Company, Kalamazoo, MI 49001, USA.
The tetracycline analogs minocycline and doxycycline are inhibitors of metalloproteinases (MMPs) and have been shown to inhibit angiogenesis in vivo. To further study the mechanism of action of these compounds we tested them in an in vitro model of angiogenesis: aortic sprouting in fibrin gels. Angiogenesis was quantitated in this system by a unique application of planar morphometry. Both compounds were found to potently inhibit angiogenesis in this model. To further characterize the activity of these compounds against MMPs, we determined the IC50S of both compounds against representatives of three classes of metalloproteinases: fibroblast collagenase, stromelysin, and gelatinase A. Doxycycline was found to inhibit collagenase, gelatinase A and stromelysin with IC50S of 452 microM, 56 microM and 32 microM, respectively. Minocycline was found to inhibit only stromelysin in the micromolar range with an IC50 of 290 microM. Since these results suggest that these compounds may not have been inhibiting in vitro angiogenesis by an MMP-dependent mechanism, we decided to test the effects of the potent MMP inhibitor BB-94. This compound failed to inhibit aortic sprouting in fibrin gels, thus strongly suggesting that both doxycycline and minocycline act by an MMP-independent mechanism. These results have implications for the mechanism of action of tetracycline analogs, particularly where they are being considered for the treatment of disorders of extracellular matrix degradation including periodontal disease, arthritis, and tumor angiogenesis.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7543375&dopt=Abstract
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