화살나무 추출물에 의한 Doxorubicin-유도 조직손상의 억제 = Reduction of Doxorubicin-induced Tissue Damage by Euonymus alatus Extract

다국어 초록 (Multilingual Abstract)

Doxorubicin(DR), a potent antineoplastic drug, is effective in adult and childhood solid tumors and hematologic cancer. However, it has minor(mucositis, nausea, vomiting and alopecia) and major(myelosuppression, cumulative dose-related cardiomyopathy, and skin and subcutaneous ulcers) clinical toxic effects. Accidental subcutaneous DR-extravasation may provoke a prolonged and severe cutaneous inflammatory reaction for which there is currently no simple and effective treatment method. Because of this, apart from measures to prevent paravenous extravasation, many methods of preventing these ulcers have been tried clinically or experimentally, but the efficacy is uncertain. The present study was undertaken to exploit Euonymus alatus extract(EA) as an antidote for DR-induced skin ulceration, using animal model, and to evaluate the effects of EA on the pharmacological activity of DR.
Sprague-Dawley rats and ICR mice were intradermally injected DR(0.5 mg/rat and 0.2 mg/ mouse) with or without EA(10 mg/rat and 5 mg/mouse). In rat model, intradermal injection of DR alone produced predictable uniform skin necrosis and ulceration involving the deep dermis. These ulcers developed within 3-7 days, remained stable for 2-4 weeks, and all rats died in 55 days of observation. However, intradermal injection of DR plus EA into rat developed only minor transient edema, erythema and mild inflammation involving the superficial dermis, which healed quickly, and all rats survived throughout the experimental periods. In mouse model, intradermal injection of DR alone produced an ulcer approximately 15.2 mm2 at 5 days. This ulcer was progressively aggravated in size until 15 days, and regressed and healed after that. But, when mice were intradermally injected DR plus EA, the ulcers were reduced in size and healed quickly. These results suggest significant efficacy for EA as a DR-extravasation antidote.
B16 cells, 3LL cells and human tonsillar lymphocytes were cultured in the presence of DR with or without EA, and the proliferation responses of these cells were evaluated. DR alone de-creased remarkably the proliferation of malignant cells as well as normal cells, in a dose-dependent fashion. On the other hand, the EA itself reduced weakly the responses of tumor cells but increased those of normal cells. And EA also slightly enhanced the DR- induced inhibition of the tumor cell-proliferation, but it restored the DR-derived decrease of the lymphocyte-prol-iferation. These results suggest that EA itself has no side effects, and also suggest that EA may possibly diminish the systemic toxic effects of DR-administration.
Taken together, the present study reveals that EA has an antidotic activity against DR-ex-travasations and systemic DR. And these results suggest the possibility that EA could be developed and used in a form of DR-annex as an antidotic and reinforcing agent of DR.