Prolonged exposure to mutagenic substances is strongly associated with an individual's risk of developing colorectal cancer. Clinical investigation of oltipraz as a chemopreventive agent is supported by its induction of the expression of detoxication enzymes in various tissues, and its protective activity against the formation of chemically induced colorectal tumors in animals. The goals of the present study were: to determine if oltipraz could induce detoxicating gene expression in human tissues; to identify effective nontoxic doses for more extensive clinical testing; and to establish a relationship between effects in the colon mucosa and those in a more readily available tissue, the peripheral mononuclear cell. 24 evaluable patients at high risk for colorectal cancer were treated in a dose-finding study with oltipraz 125, 250, 500, or 1,000 mg/m 2 as a single oral dose. Biochemical analysis of sequential blood samples and colon mucosal biopsies revealed increases in glutathione transferase activity at the 1ower dose levels. These effects were not observed at the higher doses. More pronounced changes were observed in detoxicating enzyme gene expression in both tissues at all doses. Peripheral mononuclear cell and colon mRNA content for ␥ -glutamylcysteine synthetase ( ␥ -GCS) and DT-diaphorase increased after dosing to reach a peak on day 2-4 after treatment, and declined to baseline in the subsequent 7-10 d. The extent of induction of gene expression in colon mucosa reached a peak of 5.75-fold for ␥ -GCS, and a peak of 4.14-fold for DT-diaphorase at 250 mg/m 2 ; higher doses were not more effective. Levels of ␥ -GCS and DT-diaphorase correlated closely ( P Յ 0.001) between peripheral mononuclear cells and colon mucosa both at baseline and at peak. These findings demonstrate that the administration of minimally toxic agents at low doses may modulate the expression of detoxicating genes in the tissues of individuals at high risk for cancer. Furthermore, peripheral mononuclear cells may be used as a noninvasive surrogate endpoint biomarker for the transcriptional response of normal colon mucosa to drug administration. ( J. Clin. Invest. 1996. 98:1210-1217.)

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Irinotecan can be safely administered with raltitrexed on a day-1 and day-8 schedule at 100 mg/m(2) and 3.0 mg/m(2), respectively, every 21 days. When raltitrexed was given on day 2, these doses were not tolerated, necessitating a dose reduction of the irinotecan to 75 mg/m(2). This regimen possesses clinical activity in patients with colorectal cancer.

e19519 Background: Breast cancer therapy related neurocognitive dysfunction, such as memory impairment and “chemo-brain”, has been reported by many women during and after receiving adjuvant chemotherapy. Studies evaluating this effect have had mixed results regarding its validity. No study has evaluated a specific regimen and none have examined dose dense therapy. We have serially evaluated the cognitive and quality of life changes in patients receiving dose dense adjuvant adriamycin/cyclophosphamide followed by pactitaxel (DD AT-P) chemotherapy. Methods: Patients with early stage breast cancer (Stages I, II) who were treated at a single community hospital cancer center and were given dose dense AC-P adjuvant chemotherapy were asked to participate in this trial. 45 patients were enrolled and 43 were eligible for evaluation with the following instruments: FACT-F, FAS test, MMSE, MNA and BDI. Tests were administered at the start of chemotherapy, at the completion of chemotherapy, at 6 months and 12 months after completing chemotherapy. The tests were administered by oncology nurses. Scores were evaluated using repeated measures analysis of variance testing whether or not the change from baseline test scores had a trend over time. Results: 43 patients were evaluated. Age range was 34-72 years with a median age of 52. 34 patients completed 4 evaluations, 6 completed 3 evaluations, 3 completed 2 evaluations. The only measures demonstrating significant trends were the FAS test (p=0.022) and the Functional Well-Being (p=0.002) and Physical Well-Being (p<0.0001) portions of the FACT-F. The changes over time for these measures all indicated improved performance over baseline at the completion of the trial. The remainder of the tests showed no significant change over time. Conclusions: Dose dense adjuvant chemotherapy with AC-P for breast cancer does not result in decreased cognitive or quality of life measures over time. Patients can be reassured that this specific program of therapy will not lead to long term decreases in mental function and quality of life.