کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2755440 1149817 2010 6 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Phase I Study of Temozolomide and Laromustine (VNP40101M) in Patients With Relapsed or Refractory Leukemia
موضوعات مرتبط
علوم پزشکی و سلامت پزشکی و دندانپزشکی بیهوشی و پزشکی درد
پیش نمایش صفحه اول مقاله
Phase I Study of Temozolomide and Laromustine (VNP40101M) in Patients With Relapsed or Refractory Leukemia
چکیده انگلیسی

PurposeAlthough alkylators are known to be effective against some myeloid leukemias, resistance is often mediated via O6-alkylguanine-DNA alkyltransferase (AGT). Temozolomide's inhibition of AGT may sensitize leukemia cells to the novel alkylator laromustine. We conducted a phase I translational study to evaluate the toxicities and estimate the maximum tolerated dose (MTD) of laromustine when administered with temozolomide (TMZ) in patients with hematologic malignancies.Patients and MethodsTMZ was delivered twice daily for 5 doses followed by a single infusion of laromustine. The target TMZ dose was the dose that would reliably result in > 90% AGT depletion. Once the target TMZ dose was identified, the laromustine dose was escalated. A total of 35 patients with relapsed/refractory leukemia were treated.ResultsTreatment with TMZ 300 mg for 5 doses resulted in > 90% depletion of AGT levels in 5 of 6 patients. The MTD of the combination was established at TMZ 1500 mg and laromustine 300 mg/m2. Three of the 7 patients assayed from cohort 1 achieved > 90% depletion of AGT activity (range, 77%-100% depletion; median, 88%). Five of 6 patients enrolled in cohort 2 achieved > 90% depletion of AGT activity (range, 92%-100% depletion; median, 93.5%). This established that the 300-mg dose of TMZ (1500 mg total) would be maintained in subsequent cohorts. The majority of adverse events were primarily hematologic, with infectious and pulmonary complications also noted. Three (9%) of the patients with previous refractory disease achieved a complete remission, and 5 (14%) of the patients achieved a morphologic, leukemia-free, but persistent hypocellular bone marrow status.ConclusionLaromustine in combination with TMZ is tolerable and manageable at doses that predictably suppress AGT. Reliable TMZ-induced inhibition of AGT was observed in doses that are clinically tolerable. Evidence of antitumor effect was observed with this combination, suggesting that further efficacy studies should be performed.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Clinical Lymphoma Myeloma and Leukemia - Volume 10, Issue 3, June 2010, Pages 211–216
نویسندگان
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