Pharmacologically directed ara-C therapy for refractory leukemia.
During a two-year experience treating patients with refractory acute leukemia with a fixed 12-hour schedule of high-dose ara-C, cellular ara-CTP pharmacodynamics were ascertained in circulating blasts of these patients. A strong correlation was found between achievement of complete remission and cellular ara-CTP levels. We therefore, attempted to improve the complete remission rate in patients with low ara-CTP levels by decreasing the intermittent ara-C dosing interval, thereby raising the minimum ara-CTP level in leukemic cells between doses. This initial attempt at pharmacologic direction of chemotherapy was successful in elevating minimum ara-CTP levels but did not produce an increase in response rate, probably because the total duration of ara-CTP exposure was decreased when the dose intervals were shortened. Currently we are engaged in a new approach based on the knowledge accumulated over the past three years. Patients receive a test ara-C dose from which data on ara-CTP cellular metabolism is derived, followed by a CI of ara-C at a dose calculated individually for each patient. Preliminary results of this approach thus far indicate an increased response rate and a different spectrum of toxicity than that observed with intermittent dose ara-C. Further clinical trials will determine the true effectiveness of this approach.
D001085:Arabinofuranosylcytosine Triphosphate / Q000097:blood*; D001088:Arabinonucleotides / Q000097:blood*; D003561:Cytarabine / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D004247:DNA / Q000096:biosynthesis; D004351:Drug Resistance; D006801:Humans; D007700:Kinetics; D007938:Leukemia / Q000097:blood / Q000188:drug therapy*
D001088:Arabinonucleotides; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D004247:DNA