| Malignant melanoma is tumor being well known to respond poorly to treat with chemotherapeutic reagents, and no any drug was very curative effect on it. There were no significant development about chemotherapecutive drugs which used for melanoma in recent years. The side effect had been ascending following curative effect when combine therapy with two drug such as DTIC and others, so it is of great to develop new therapeutic means for melanoma patients, especially for those resistant to conventional chemotherapecutive drugs.Studies indicated that a low concentration of some arsenic compounds have some benefits to human physiology, such as stimulation of human hematopoiesis. The use of arsenic compounds as a drugs has a longer history in Chinese traditional medicine. For instance, on some human diseases such as psoriasis, syphilis, and rheumatosis, including topical preparation of treatment for patients with melanoma and vitiligo. In the early 1970's, it was introduced to treat acute promyelocytic leukemia (APL) and chronic myeloid leukemia (CML), and it was showed surprising clinical efficacy. In 1996, As2O3 was found could induce apoptosis and differentiation in NB4 cell, its molecule mechanism had been profound investigated. Clinical studiesshowed that As2O3 is an effective and relatively safe drug in the treatment of acute promyelocytic leukemia (APL). No obvious toxic reactions were found when As2O3 was given by iv drip, which is appropriate.In this study, we investigated the possible cellular and molecular mechanisms of As2O3 treatment by using S91 cells, an mouse melanoma cell lines and C57BL/6 mouse bearing melanoma, as in vivo and vitro model. The results showed that AS2O3 could induce differentiation and apoptosis in melanoma cells. Our studies were divided in two parts as follows.1.Effects of arsenic trioxide (As2O3) on the mouse melanoma S91 cell line in vitroIn this report we investigated the effects of different concentrations of As2O3 on cultured Cloundman S91 cells. The results indicated that As2O3 had dose-dependent dual effects on APL cells: inducing preferentially apoptosis at high concentrations ( > 2umol/L), and promoting cell growth obviously inducing partial differentiation at low concentrations (0.1 to 0.25 umol/L). Induction of apoptosis was enhanced with increase of concentration and time of As2O3. Treatment of S91 cells for 72h with low dose As2O3 enhanced the tyrosinase activity and melanin content, this effect was blocked by TPA, a activator of protein kinase C (PKC). In conclusion, combination of induction of apoptosis and partial differention could be the main cellular mechanisms of As2O3 in the treatment of melanoma,and PKC may play an important role in determining the specific effects of As2O3 on melanoma cells.The above study showed antitumor effects of AS2O3 in S91 cell that could not be compared with those of APL. As2O3 concentrations used in this study were higher than used in studies done on hematological cancers while AS2O3 induced apoptosis. At clinically obtainable As2O3 concentrations (<2 uM), all of the studies failed to induce total cell death. These facts suggest that to potentiate cytotoxicity of As2O3 at low concentrations, it is essential to develop the enhancer of As2O3 toxicity. we explore the proliferation and apoptosis rate of cell line CloundmanS91 induced by combined arsenic trioxide with ascorbic acid. S91 cells were treated with 100 u mol/L ascorbic acid and 2 u mol/L arsenic trioxide for 72h. Combination of arsenic trioxide with ascorbic acid markedly inhibited the proliferation ability and increased apoptosis rate of S91 cells. In future, combined therapy that uses As2O3 together with AA may prove useful for treating melanoma.2. Effect of arsenic trioxide with ascorbic acid on experimental melanoma bearing miceTo investigate the effect of As2O3 on melanoma in vivo, we established skin melanoma models of B16 cell line in C57BL/6 mice. The results showed 6 days later, punctate, linear and nodal even kaulifloweroid melanoma were seen...
|
PDF Full Text Request