Biomedical subjects
Publications and source records attributed to Mark J Ratain.
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PURPOSE: O6-benzylguanine (BG) provides a means to effectively inactivate the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) and increase the chemotherapeutic effectiveness of chloroethylating and methylating agents in preclinical and clinical studies. Two different doses of BG have been reported as the optimal biochemical modulatory dose for patients (i.e., 100 and 120 mg/m2). The objective of our study was to compare these doses by measuring AGT in surgically removed specimens after treatment with BG. EXPERIMENTAL DESIGN: BG was administered to patients as an i.v. infusion 16 +/- 4 h before surgical resection of their systemic tumor. AGT activity was measured in the tumor using a methylated DNA substrate. The target end point was defined as > or =11 of 13 patients with undetectable tumor AGT levels (<10 fmol/mg protein). RESULTS: Of the 28 patients enrolled, 25 of whom were analyzed for AGT activity, the most common primary sites of cancer included the colon (n = 11), bladder (n = 3), rectum (n = 4), and stomach (n = 3). Positive (DaOY cells) and negative (Chinese hamster ovary cells) control cell lines were included in each assay. Seven of the 12 patients treated with 100 mg/m2 BG had AGT activity of >10 fmol/mg protein (15-147 fmol/mg protein). Only 2 of the 13 patients treated with 120 mg/m2 BG had AGT activity of >10 fmol/mg protein (11 and 12 fmol/mg protein). CONCLUSIONS: From our surgically removed tissue data, a dose of 120 mg/m2 BG is recommended to deplete systemic tumors of AGT activity.
PURPOSE: The purpose of this study was to determine the toxicity of escalating doses of trastuzumab when combined with a fixed dose regimen of interleukin (IL)-2. EXPERIMENTAL DESIGN: Eligible patients had nonhematological malignancies for which standard therapy did not exist or was no longer effective and had tumors that overexpressed HER2. IL-2 was initially administered at a dose of 1.25 million IU/m(2) (low dose) s.c. daily except for 3 days every 2 weeks, when it was given at a dose of 15 million IU/m(2) (intermediate dose). These doses were reduced to 1.0 million and 12 million IU/m(2) after the first 18 patients. Trastuzumab was administered i.v. just before the first intermediate IL-2 dose and was escalated in cohorts of six or more patients from 1 mg/kg every 2 weeks to 8 mg/kg weekly. In vitro cytotoxicity testing was performed with patient peripheral blood mononuclear cells and HER2-overexpressing cell lines. RESULTS: Forty-five patients were treated. Dose-related toxicity from trastuzumab was not observed. IL-2-related toxicities such as fever, chills, and fatigue were less common with the reduced doses of IL-2. There were two grade 3 and three grade 4 pulmonary reactions. Four major responses were observed, all in breast cancer patients treated with trastuzumab doses of at least 4.0 mg/kg. Although IL-2 produced expansion of natural killer cell subsets, there was no correlation between in vitro cytotoxicity and clinical response. CONCLUSIONS: A regimen of IL-2 combined with trastuzumab is feasible, and response numbers are encouraging. Further testing of this regimen is warranted if the pulmonary toxicity can be ameliorated.