Relationship between colorectal cancer glutathione levels and patient survival: early results.

PURPOSE: Elevated glutathione is a cause of resistance to anticancer agents and x-rays. The purpose of this study was to determine the frequency and clinical significance of glutathione elevation in human colorectal cancer. METHODS: Glutathione levels were measured in 41 colon cancers, 24 rectal cancers, and corresponding normal tissues. The patients were then followed up prospectively for tumor recurrence and survival. Survival was analyzed by the Kaplan-Meir method and Cox proportional hazards regression. RESULTS: Glutathione levels in primary colorectal cancers were significantly higher than in the corresponding normal tissues. Elevated glutathione levels had a significant negative effect on survival in patients with colorectal cancer, whether based on the mean (P = 0.02) or median (P = 0.04) normal tissue levels. A negative effect of glutathione levels on survival was apparent in patients with colorectal cancer, whether or not they were treated with postoperative therapy. The larger the ratio of tumor glutathione to normal tissue glutathione, the poorer the prognosis. When adjusted for other covariates, glutathione was still a significant predictor of survival. CONCLUSIONS: An elevated tumor glutathione level at the time of diagnosis appears to confer a poor prognosis in patients with colorectal cancer. Longer-term study using a larger number of patients will be required to confirm these findings. Knowledge of tumor glutathione content may help identify patients requiring more intensive therapy.

Intratumor variability in prognostic indicators may be the cause of conflicting estimates of patient survival and response to therapy.

The DNA index, percentage of S-phase cells, proliferation fraction, and glutathione (GSH) content were determined at more than 1100 separate sites in 140 human tumors and 140 normal tissues. The study showed that the variability was so great from site to site within a tumor that there was only a 61% chance of identifying an aneuploid tumor clone (when present) if only a single site sample was analyzed for DNA content. Similar broad variability was observed in the percentage of S-phase cells, proliferation fraction, and glutathione content. Since these tumor characteristics are often used to predict the outcome of therapy and patient survival, the inaccuracy and underestimation of the test results may cause conflicting or erroneous predictions. The probability of finding an aneuploid clone or elevated percentage of S-phase cells proliferation fraction and GSH content increased dramatically as the number of sample sites studied per tumor was increased. Statistical analyses indicated that in order to achieve a 90% probability that the test results for these parameters were representative of the whole tumor: (a) all single site testing should be abandoned; (b) assays should be performed on samples taken from 3-7 different sites within each tumor; or (c) samples from each tumor should be pooled and the analyses run on a thoroughly mixed or homogenized aliquot of the multisite sample.

The Sézary syndrome: a malignant proliferation of helper T cells.

The Sézary syndrome is a frequently lethal disease characterized by circulating malignant cells of thymus-derived (T)-cell origin. The capacity of circulating malignant lymphocytes from patients with this syndrome to synthesize immunoglobulins and to function as helper or suppressor cells regulating immunoglobulin synthesis by bone marrow-derived (B) lymphocytes was determined. Peripheral blood lymphocytes from normal individuals had geometric mean immunoglobulin synthetic rates of 4,910 ng for IgM, 1,270 ng for IgA, and 1,625 ng for IgG per 2 X 10(6) cells in culture with pokeweed mitogen for 7 days. Purified normal B cells had geometric mean synthetic rates of 198 ng for IgM, 145 ng for IgA, and 102 ng for IgG. Leukemic cells from patients with the Sézary syndrome produced essentially no immunoglobulins. Adding normal T cells to normal B cells restored their immunoglobin producing capacity. Leukemic cells from four of five patients tested had a similar capacity to help immunoglobulin synthesis by purified normal B cells. Additionally, Sézary cells from one patient studied induced a nearly 10-fold increase in IgA synthesis by lymphocytes from a child with ataxia telangiectasia and selective IgA deficiency. Furthermore, these Sézary cells induced more than a 500-fold increase in IgG and IgA synthesis by lymphocytes from a child with Nezelof's syndrome. When Sézary cells were added to normal unfractionated lymphocytes, they did not suppress immunoglobulin biosynthesis. In addition, unlike the situation observed when large numbers of normal T cells were added to purified B cells, there was no depression of immunoglobulin synthesis at very high malignant T-cell to B-cell ratios. These data support the view that Sézary T cells do not express suppressor cell activity. The results presented in this paper suggest that neoplastic lymphocytes from the majority of patients with the Sézary syndrome originate from a subset of T cells programmed exclusively for helper-like interactions with B cells in their production of immunoglobulin molecules.