Safety and efficacy of decitabine in combination with temozolomide in metastatic melanoma: a phase I/II study and pharmacokinetic analysis.

BACKGROUND: Temozolomide (TMZ) is widely used for chemotherapy of metastatic melanoma. We hypothesized that epigenetic modulators will reverse chemotherapy resistance, and in this article, we report studies that sought to determine the recommended phase 2 dose (RP2D), safety, and efficacy of decitabine (DAC) combined with TMZ. PATIENTS AND METHODS: In phase I, DAC was given at two dose levels: 0.075 and 0.15 mg/kg intravenously daily × 5 days/week for 2 weeks, TMZ orally 75 mg/m(2) qd for weeks 2-5 of a 6-week cycle. The phase II portion used a two-stage Simon design with a primary end point of objective response rate (ORR). RESULTS: The RP2D is DAC 0.15 mg/kg and TMZ 75 mg/m(2). The phase II portion enrolled 35 patients, 88% had M1c disease; 42% had history of brain metastases. The best responses were 2 complete response (CR), 4 partial response (PR), 14 stable disease (SD), and 13 progressive disease (PD); 18% ORR and 61% clinical benefit rate (CR + PR + SD). The median overall survival (OS) was 12.4 months; the 1-year OS rate was 56%. Grade 3/4 neutropenia was common but lasted >7 days in six patients. CONCLUSIONS: The combination of DAC and TMZ is safe, leads to 18% ORR and 12.4-month median OS, suggesting possible superiority over the historical 1-year OS rate, and warrants further evaluation in a randomized setting.

Influence of smokeless tobacco exposure on detoxification status and chromosomal damage in male and female habitues.

In India, a large number of tobacco chewers and masheri users are chronically exposed to tobacco genotoxicants. Detoxification processes involving cellular glutathione (GSH) and glutathione S-transferases (GST) determine the outcome of exposure to environmental mutagens including those present in tobacco. Hence, in this study, GSH levels, GST activity, GSTM1 genotype and cytogenetic damage were determined using lymphocytes from 114 smokeless tobacco habitues and controls. The study groups comprised of male tobacco chewers, female masheri users, and age- and sex-matched controls. Irrespective of the tobacco habit, GSH levels and GST activity were higher in females than in males. In both the groups of habitues, GSH levels were similar to those in controls, while a significant reduction in GST activity was observed in tobacco chewers only. The frequency of cytogenetic alterations was significantly elevated in both the groups of habitues with respect to controls. However, break-type aberrations were more frequent in tobacco chewers while gaps were commonly observed in masheri users. Differences in the nature of chromosomal alterations in the two groups of habitues appeared to be related to variation in total tobacco exposure and gender-related differences in the efficacy of the GSH/GST detoxification system.

Biological monitoring of bidi industry workers occupationally exposed to tobacco.

Ambient and biological monitoring was undertaken among tobacco processors who are chronically exposed to tobacco particulates via nasopharyngeal and cutaneous routes. Ambient monitoring revealed that the inspirable dust concentration was 150-fold higher in the tobacco factory than in the control environment, and was associated with chronic bronchitis in workers. Increased systemic exposure to tobacco constituents was evident from the high levels of cotinine, thioethers, promutagens and direct acting mutagens in workers' urine. The mean glutathione level and glutathione S-transferase activity were significantly lower in the peripheral blood lymphocytes of workers; however, the frequency of the GSTM1 null allele was similar to that in controls. A significant increase in chromosomal damage was noted in target and non-target cells of tobacco processors. In view of the association between tobacco use and several non-communicable diseases, the findings of the present study indicate an urgent need to minimize tobacco exposure among the processors.