Melatonin and Metformin Failed to Modify the Effect of Dacarbazine in Melanoma

Lessons Learned

• Melatonin did not increase the efficacy of systemic chemotherapy in melanoma.
• Metformin did not increase the efficacy of systemic chemotherapy in melanoma.

     

Phase II trial of Paclitaxel and Dacarbazine with filgrastim administration in advanced malignant melanoma

A Phase II trial was conducted in patients with advanced malignant melanoma with intravenous Paclitaxel and Dacarbazine (DTIC). The initial starting dose for Paclitaxel was 135 mg/m² followed by DTIC 800 mg/m². Due to the lack of myelosuppression and other toxicities, the starting dose for Paclitaxel was escalated to 250 mg/m² and the dose for DTIC escalated to l000 mg/m². Twenty-five patients were enrolled in this study. Among the 25 patients assessable for response, three patients had a partial response with a response rate of 12% (CI 3-31%) and one patient had stable disease. Three additional patients showed evidence of anti-tumor activity with minor responses. For patients who had no prior chemotherapy or biochemotherapy, the response rate was 20%. Toxicity was generally tolerable and included mainly neurotoxicity from Paclitaxel. At the doses and schedule used, the combination of Paclitaxel and DTIC did not appear to increase the response rate compared to each agent used singly.     

Effect of a novel somatostatin analogue combined with cytotoxic drugs on human tumour xenografts and metastasis of B16 melanoma

A novel somatostatin analogue, TT-232 (which inhibits the proliferation of various cell cultures and transplantable mouse tumours), was examined regarding its effect on human melanoma and lymphoma xenografts as a single treatment or in combination with DTIC (dacarbazine) and etoposide. TT-232 inhibited the growth of HT-18 melanoma xenografts, a dose of 5 mg kg(-1) being the most effective. Combination of 1 mg kg(-1) TT-232 with 30 or 60 mg kg(-1) DTIC (administered daily) resulted in a stronger inhibitory effect compared to TT-232 or DTIC as a single modality. Antimetastatic effect of TT-232 treatment combined with DTIC was studied using the B16 mouse melanoma muscle - lung metastasis model. The number of lung metastases of B16 melanoma could be decreased by the daily administration of 1 mg kg(-1) TT-232 or 60 mg kg(-1), but not of 30 mg kg(-1) DTIC. TT-232, combined with 30 or 60 mg kg(-1) DTIC decreased the lung metastasis number significantly lower than the control. Nearly 50% growth inhibition of HT-58 lymphoma was achieved by daily treatment with 1 mg kg(-1) TT-232. 5 mg kg(-1) etoposide, administered daily, resulted in a similar effect. The combination of 1 mg kg(-1) TT-232 and 5 mg kg(-1) etoposide was significantly more effective than TT-232 or etoposide as a single treatment. The very strong tumour growth inhibitory effect of 10 mg kg(-1) etoposide could even be increased by combination with TT-232. These experimental data suggest that TT-232 may be an effective new tool in the combination chemotherapy of malignant tumours like melanoma and lymphoma.     

Prospective Randomized Comparison of Dacarbazine (DTIC) Versus DTIC Plus Interferon-Alpha (IFN-α) in Metastatic Melanoma

Dacarbazine (DTIC) has been the mainstay of chemotherapy for metastatic melanoma for over two decades, but only 15%–20% of patients respond and benefit is usually transient. Randomized studies combining DTIC with interferon-alpha (IFN-α) in advanced disease have so far been inconclusive in terms of response and survival.We report a randomized prospective pilot Phase III trial of DTIC ±IFN-a in patients with metastatic melanoma. The primary endpoint was death. A total of 61 patients were randomized between April 1995 and April 1998. Differences in survival between groups were assessed using log-rank analysis. Quality of life was measured using the European Organization for Research on Treatment of Cancer QLQ C30 (+3) questionnaire. Fifty-seven patients died during the study. The median survival for patients receiving DTIC was 7.2 months (95% confidence interval (CI) 4.4–9.0); it was 4.8 months for DTIC + IFN-α (95% CI 2.0–8.0). There was no significant difference in survival between the two treatment arms (χ²_unadjusted = 0.15, P = 0.70; χ²_adjusted = 0.01, P = 0.91). The 6-month survival of those patients randomized to DTIC alone was 58% compared with 40% for those patients randomized to DTIC + IFN-α. There were no differences in quality of life between treatment groups.This study failed to demonstrate a survival benefit for patients receiving IFN-α in combination with DTIC. These results are inconclusive primarily owing to the small size of the trial. A meta-analysis is required to determine whether there is a role for the addition of IFN-α to DTIC in the treatment of this disease.     

Investigation of the Pristine and Functionalized Carbon Nanotubes as a Delivery System for the Anticancer Drug Dacarbazine: Drug Encapsulation

Carbon Nanotubes (CNTs) have been used as the systems in drug delivery due to their exceptional physical and chemical properties. In this study, the adsorption of an anticancer drug Dacarbazine (DAC) into the inner and outer surface of pristine and Functionalized Carbon Nanotubes (FCNTs) with four carboxylic acid groups was investigated in aqueous solution using the Molecular Dynamics (MD) simulations. Our simulation results showed that in spite of the adsorption of drug molecules on the outer sidewall of pristine and functionalized nanotubes, the spontaneous encapsulation of DAC molecule into the cavity of CNTs and FCNTs is observed. The simulations show that the arrangement of the DAC molecule into the CNTs and FCNTs is controlled by π-π interactions.     

Enhanced anti-tumor activity by the combination of a conditionally replicating adenovirus mediated interleukin-24 and dacarbazine against melanoma cells via induction of apoptosis

Malignant melanoma is one of the most lethal and aggressive human malignancies. It is notoriously resistant to all of the current therapeutic modalities, including chemotherapy. Suppressed apoptosis and extraordinary invasiveness are the distinctive features that contribute to the malignancy of melanoma. Dacarbazine (DTIC) has been considered as the gold standard for melanoma treatment with a response rate of 15–20%. Unfortunately, the resistance to this chemotherapeutic agent occurs frequently. ZD55-IL-24 is a selective conditionally replicating adenovirus that can mediate the expression of interleukin-24 (IL-24) gene, which has a strong anti-tumor effect. In this study, we hypothesized that a combination of ZD55-IL-24-mediated gene virotherapy and chemotherapy using DTIC would produce an increased cytotoxicity against human melanoma cells in comparison with these agents alone. Our results showed that the combination of ZD55-IL-24 and DTIC significantly enhanced the anti-tumor activity by more effectively inducing apoptosis in melanoma cells than either agent used alone without any overlapping toxicity against normal cells. This additive or synergistic effect of ZD55-IL-24 in combination with DTIC in killing human malignant melanoma cells implies a promising novel approach for melanoma therapy.     

Role of MGMT as biomarker in colorectal cancer

O⁶-methylguanine DNA methyltransferase (MGMT) gene promoter methylation plays an important role in colorectal carcinogenesis, occurring in about 30%-40% of metastatic colorectal cancer. Its prognostic role has not been defined yet, but loss of expression of MGMT, which is secondary to gene promoter methylation, results in an interesting high response to alkylating agents such as dacarbazine and temozolomide. In a phase 2 study on heavily pre-treated patients with MGMT methylated metastatic colorectal cancer, temozolomide achieved about 30% of disease control rate. Activating mutations of RAS or BRAF genes as well as mismatch repair deficiency may represent mechanisms of resistance to alkylating agents, but a dose-dense schedule of temozolomide may potentially restore sensitivity in RAS-mutant patients. Further development of temozolomide in MGMT methylated colorectal cancer includes investigation of synergic combinations with other agents such as fluoropyrimidines and research for additional biomarkers, in order to better define the role of temozolomide in the treatment of individual patients.     

MITF基因扩增预测重组人血管内皮抑素联合达卡巴嗪一线治疗晚期黑色素瘤疗效的临床研究

目的 探讨小眼畸形相关转录因子（MITF）基因扩增对重组人血管内皮抑素（恩度）联合达卡巴嗪一线治疗晚期黑色素瘤的疗效预测作用。方法 收集60例接受恩度联合达卡巴嗪一线治疗晚期黑色素瘤患者的石蜡包埋组织样本,采用实时定量PCR检测MITF基因扩增,观察患者的疾病控制率和远期疗效。结果 56例晚期黑色素瘤样本成功检测,MITF基因扩增率为51.8％（29／56）,其中肢端、非肢端皮肤、黏膜、原发不明黑色素瘤中的MITF基因扩增率分别为31.2％、63.2％、80.0％和36.4％（P=0.050）。MITF基因扩增组与无扩增组患者接受恩度联合达卡巴嗪治疗的疾病控制率分别为58.6％（17／29）和81.5％（22／27）,差异无统计学意义（P=0.063）;两组的中位无进展生存期分别为6.4个月（95％CI：0.5～12.2个月）和8.4个月（95％CI：6.8～10.3个月）,差异亦无统计学意义（P=0.169）。结论 中国晚期黑色素瘤患者MITF基因扩增率较高,检测MITF基因扩增可能有助于预测恩度联合达卡巴嗪治疗晚期黑色素瘤的疗效,总生存结果有待进一步随访。     

促红细胞生成素对达卡巴嗪抗小鼠黑色素瘤细胞活性的调节作用

目的检测小鼠黑色素瘤细胞株B16促红细胞生成素受体(Erythropoietin receptor,EPOR)的表达,探讨促红细胞生成素(Erythropoietin,EPO)对达卡巴嗪抗B16细胞活性的影响及与Bcl-2家族蛋白表达的关系。方法采用RT-PCR、免疫荧光和激光共聚焦显微镜、Western blot等方法检测B16 细胞EPOR mRNA和蛋白的表达。MTT法和克隆形成试验检测EPO与达卡巴嗪联合应用时对B16细胞增殖的影响。Western blot法检测EPO对B16细胞Bcl-2、Bcl-xL、Bax蛋白表达的影响。结果B16细胞表达EPOR mRNA和蛋白。EPO能有效减少达卡巴嗪诱导B16细胞的凋亡（P<0.05）,EPO作用后,B16细胞Bcl-2、Bcl-xL蛋白表达水平明显增加（P<0.05）,Bax蛋白表达水平未见明显变化。结论B16细胞表达EPOR,EPO可调节化疗药对B16细胞的作用,其作用机制可能与其影响Bcl-2家族蛋白表达有关。