Elevated frequencies of 6-thioguanine-resistant lymphocytes in multiple sclerosis patients treated with cyclophosphamide: a prospective study

• Published in: Mutation Research/Genetic Toxicology Vol. 204; no. 3; pp. 509 - 520
• Main Authors: Ammenheuser, M.M., Ward, J.B., Whorton, E.B., Killian, J.M., Legator, M.S.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.1988
• Subjects: 6-Thioguanine-resistant; Autoradiography; Cyclophosphamide; Cyclophosphamide - adverse effects; Drug Resistance; Humans; Lymphocytes; Lymphocytes - drug effects; Multiple sclerosis; Multiple Sclerosis - drug therapy; Mutagens; Peripheral blood; Prospective Studies; Smoking; T lymphocytes; Thioguanine - pharmacology; Time Factors; T lymphocytes; Multiple sclerosis; Cyclophosphamide; 6-Thioguanine-resistant; Lymphocytes; Peripheral blood
• ISSN: 0165-1218; 0027-5107
• DOI: 10.1016/0165-1218(88)90045-6

An autoradiographic assay for 6-thioguanine-resistant (TG r) lymphocytes was used to determine the frequency of in vivo derived variant T lymphocytes in peripheral blood from multiple sclerosis (MS) patients treated with monthly intravenous infusions of 750 mg/m 2 of cyclophosphamide (CP). To analyze the time-course of response to CP, the MS patients were studied prospectively. Samples were obtained from the patients before the beginning of CP therapy, 4–5 times during the course of treatment, and, finally, 2 or 3 months after the completion of therapy. 2 weeks after the first CP infusion, the variant frequencies ( Vfs) of the MS patients were significantly increased ( p < 0.05) above their pre-treatment values, but by 4 weeks following the first CP infusion the Vfs had fallen to normal or near-normal levels. After subsequent treatments, the frequencies of variant TG r cells were again higher than pre-treatment VfMs. However, within 7–13 weeks after the cessation of CP therapy, the Vfs of all subjects had returned to normal levels. The transient nature of the response indicates rapid in vivo selection against CP-induced TG r mutant cells. The mean pre-treatment Vf of the 4 MS patients who were cigarette smokers was 6.56 × 10 −6 which was significantly greater ( p < 0.05) than the mean Vf (1.52 × 10 −6) of the 4 MS patients who were non-smokers. The mean Vf from 8 assays of healthy non-smokers was 1.92 × 10 −6.