Elevated frequencies of 6-thioguanine-resistant lymphocytes in multiple sclerosis patients treated with cyclophosphamide: a prospective study.
An autoradiographic assay for 6-thioguanine-resistant (TGr) 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/m2 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 less than 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 TGr cells were again higher than pre-treatment Vfs. 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 TGr mutant cells. The mean pre-treatment Vf of the 4 MS patients who were cigarette smokers was 6.56 X 10(-6) which was significantly greater (p less than 0.05) than the mean Vf (1.52 X 10(-6) of the 4 MS patients who were non-smokers. The mean Vf from 8 assays of healthy non-smokers was 1.92 X 10(-6).
Ammenheuser
M M
MM
Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston 77550.
Ward
J B
JB
Whorton
E B
EB
Killian
J M
JM
Legator
M S
MS
D001345:Autoradiography; D003520:Cyclophosphamide / Q000009:adverse effects*; D004351:Drug Resistance; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects*; D009103:Multiple Sclerosis / Q000188:drug therapy*; D009153:Mutagens; D011446:Prospective Studies; D012907:Smoking; D013866:Thioguanine / Q000494:pharmacology; D013997:Time Factors
D009153:Mutagens; D003520:Cyclophosphamide; D013866:Thioguanine