Abstract
ABSTRACTClinical resistance to ara‐C is dose and schedule dependent. Patients refractory to or who have relapsed on combinations of drugs which include standard doses of ara‐C (100–200 mg/m2 daily for 5 to 7 days) can be induced into clinical remissions with high dose ara‐C (HiDAC). The interaction between HiDAC and asparaginase is schedule‐dependent; pharmacologic synergy and an improvement in the therapeutic index occurring with sequential HiDAC→Asparaginase. This combination has been applied in clinical trial: ara‐C 3 g/m2 as a 3 hr IV infusion was given every 12 hrs for 4 doses. At the end of the 4th infusion, 6000 IU/m2 asparaginase was given IM. This therapy was given on days 1 and 8. Refractory/ relapsed patients had a 68% complete remission rate. Treatment of 49 patients with previously untreated ANLL was associated with an 80% and 40% complete remission rate in patients <60 and >60 years of age, respectively. Median time to complete remission for both age groups was 30 days. The lower complete remission rate in older patients reflects higher induction deaths (ID) (50%), not innate drug resistance. Laboratory investigations have focused on the biochemical pharmacology of HiDAC in an attempt to explain the unique therapeutic utility of this mode of drug administration. These data suggest that human leukemia cells transport ara‐C across the cell membrane relatively less efficiently than experimental leukemia cells. The systemic metabolite of ara‐C, ara‐U, may also influence the drug's effect. In the murine leukemia L5178Y, both in vitro and in vivo, high concentrations of ara‐U are cytostatic in S‐phase. the phase of the cell cycle wherein ara‐C cytotoxicity is increased. In vivo, high concentrations of ara‐U also retard systemic deamination of ara‐C as well as its renal excretion. These features increase the terminal half‐life of HiDAC in the plasma and thus prolong cellular exposure to the drug. The interactions between ara‐U and ara‐C thus invoke selfpotentiation of HiDAC.
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