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  • Title: Chemotherapy of leukemia in mice, rats, and humans relating time of humoral stimulation, tumor growth, and clinical response.
    Author: Burke PJ, Karp JE, Vaughan WP.
    Journal: J Natl Cancer Inst; 1981 Sep; 67(3):529-38. PubMed ID: 6944525.
    Abstract:
    Studies were conducted in the leukemic mouse and rat to test the hypothesis that enhanced effects of drugs given in sequence relate to a predictable increase in tumor growth and sensitivity to cycle-active agents. The rationale is based on a) evidence that, following drug-induced aplasia, resultant bone marrow proliferation in vivo corresponds temporally with induced humoral stimulatory activity, and on b) models that demonstrate increased cytotoxicity of beta-cytosine arabinoside (Ara-C) to myeloblasts cultured in humoral stimulatory activity (HSA). CD2F1 mice bearing L-1210 leukemia received a course of 60 mg Ara-C/kg every 8th hour (q.8 h) three times on day 0 and on another day in sequence (0,1 through 0,7). The longest survival (250% of controls) was in animals whose second course began on day 3, the time of peak HSA as measured by DNA synthesis induced in L-1210 cells in culture. LBN rats bearing acute myelocytic leukemia (AML) were treated with 100 mg Ara-C/kg q.8 h six times beginning on day 0 and on other days in sequence (0,1 through 0,12). The longest survival was in those treated on day 0,6 (760% of controls), the time of peak serum stimulation, and tumor labeling index (LI). Thirty-seven patients with AML received a single course of therapy with 45 mg Ara-C/kg by a 72-hour infusion and 1.0 mg daunorubicin/kg every day three times. On day 8, the time of peak HSA and tumor LI, Ara-C was again infused. Complete remission was achieved in 56% (65% of all patients less than 60 yr old) with a single cycle of therapy. Median duration of chemotherapy-free remission was 10 months. Of 11 relapsing patients, 8 achieved a second remission with the same regimen. These studies demonstrated that the amount of proliferation of residual tumor and thereby sensitivity to cycle-active drugs given in sequence relates to the initial drug effect on tumor proliferation and the induction of humoral stimulation.
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