All-trans retinoic acid for the treatment of AIDS-related Kaposi's sarcoma: results of a pilot phase II study.
All-trans retinoic acid for the treatment of AIDS-related Kaposi's sarcoma: results of a pilot phase II study.
复制标题
DOI：
--
复制
发表时间：
1994
期刊：
影响因子：
11.4
通讯作者：
P. Gill;B. Espina;T. Moudgil;S. Kidane;J. Esplin;A. Tulpule;A. Levine
中科院分区：
文献类型：
--
作者：
P. Gill;B. Espina;T. Moudgil;S. Kidane;J. Esplin;A. Tulpule;A. Levine
维甲酸类化合物在多种恶性和癌前状态下具有抗肿瘤活性。由于Kaposi肉瘤在体内和体外都受到类固醇激素的调节，我们推测维甲酸可能在艾滋病相关的Kaposi肉瘤中具有抗肿瘤作用。因此，27例皮肤粘膜、非内脏艾滋病相关的卡波西肉瘤患者接受了全反式维甲酸(Tra)治疗。最初的起始剂量为150毫克/平方米，耐受性较差，因此随后的患者接受每周剂量递增治疗，从45毫克/平方米(每天给药，分次给药)开始，到150毫克/平方米的目标剂量(每天分三次给药)。近一半(46%)的患者有广泛的黏膜皮肤病，超过25个皮损。没有患者之前接受过细胞毒性化疗。10例患者的CD4淋巴细胞数大于或等于200个/mm~3(层I)，17例患者的CD_4细胞数低于200个/mm~3(层II)。平均每天给药剂量的中位数为150 mg(90 mg/m2；两个层次之间的剂量耐受性没有显著差异)。不良反应包括65%的患者出现一过性轻到中度头痛，61%的患者出现轻度到中度的皮肤干燥和唇炎，31%的患者出现恶心和呕吐。血液学毒性包括62%的高甘油三酯血症，23%的贫血，23%的中性粒细胞减少。在可评估的24例患者中，有4例(17%)观察到部分反应，发生在治疗12、20、24和28周后，持续4-24周。三名应答者有基线的CD4淋巴细胞计数&200/mm~3。另有3名患者的测量指标皮损减少了25%以上但不到50%，7名患者的病情稳定了16周或更长时间。在可评估的患者中，疾病进展的中位时间为22周，所有患者的总中位生存期为27.3个月。随着时间的推移，没有观察到CD4淋巴细胞计数、p24抗原和β2微球蛋白的显著变化。然而，在服用tra时，可溶性IL-2受体水平显著升高(p=0.037)。我们的结论是，tra对艾滋病相关的黏膜皮肤卡波西肉瘤患者具有活性，毒性可接受。TrA在不上调HIV参数的情况下具有免疫作用。有必要进行更多的联合研究或用更活跃的维甲酸进行研究。
Retinoids have anti-tumor activity in several malignant and premalignant conditions. Since Kaposi's sarcoma is regulated by steroid hormones both in vivo and in vitro, we hypothesized that retinoids may have anti-tumor effects in AIDS-related Kaposi's sarcoma. Thus, 27 patients with mucocutaneous, non-visceral AIDS-related Kaposi's sarcoma were treated with all-trans retinoic acid (tRA). Poor tolerance was observed at the initial starting dose of 150 mg/m2, and thus subsequent patients were treated using a weekly dose escalation, starting with 45 mg/m2 (given daily, in subdivided doses), to the target dose of 150 mg/m2 (given daily in three subdivided doses). Nearly half (46%) of the patients had extensive mucocutaneous disease with over 25 lesions. No patient had received prior cytotoxic chemotherapy. Ten patients had CD4 lymphocytes of 200/mm3 or greater (strata I); and 17 had under 200/mm3 CD4 lymphocytes (strata II). The median of the average daily tRA dose administered was 150 mg (90 mg/m2; there was no significant difference in the dose tolerance between the two strata). Adverse effects consisted of transient mild to moderate headaches in 65% of patients, mild to moderate skin dryness and cheilitis in 61%, and nausea and vomiting in 31%. Hematologic toxicities included hypertriglyceridemia in 62%, anemia in 23%, and neutropenia in 23%. Partial response to therapy was observed in 4/24 (17%) evaluable patients, occurring after 12, 20, 24, and 28 weeks of therapy, and lasting 4-24 weeks. Three responders had baseline CD4 lymphocyte counts < 200/mm3. Three additional patients experienced reduction in measured indicator lesions of greater than 25% but less than 50%, and seven patients experienced disease stabilization of 16 weeks or greater. In evaluable patients, the median time to disease progression was 22 weeks and the overall median survival in all patients was 27.3 months. No significant changes in CD4 lymphocyte counts, p24 antigen, and beta 2 microglobulin were observed over time. However, a statistically significant increase was observed in soluble IL-2 receptor levels while on tRA (p = 0.037). We conclude that tRA has activity in patients with mucocutaneous AIDS-related Kaposi's sarcoma with acceptable toxicity. tRA has immunological effects without upregulation of HIV parameters. Additional studies in combinations or with more active retinoids are warranted.