Summary
In the bench to bedside development of drugs to treat patients with cancer, the common guide to dose and schedule selection is toxicity to normal organs patterned after the preclinical profile of the drug. An understanding of the cellular pharmacology of the drug and specifically the cellular targets linked to the drug's effect is of substantial value in assisting the clinical investigator in selecting the proper dose and schedule of drug administration. The clinical development of ara-C for the treatment of acute myeloid leukemia (AML) provides a useful paradigm for the study of this process. An understanding of the cellular pharmacology, cytokinetics and pharmacokinetics of ara-C in leukemic mice showed substantial schedule-dependency. Exposure to high doses for a short duration (C × t) resulted in a palliative therapeutic outcome. In marked contrast, exposure to lower doses for a protracted period (c × T) was curative. Clinical use of ara-C in patients with AML patterned after the murine experience, c × T approach, has been of limited benefit in terms of long-term disease-free survival. Studies with human leukemia blasts from patients have shown that for the majority of patients, the initial rate-limiting step is membrane transport, the characteristics of which are substantially affected by extracellular drug concentration (dose). This pharmacologic impediment is eliminated with the blood levels attained during the infusion of gram doses (1–3 gm/m2) of the drug (high-dose ara-C, HiDaC) for shorter periods of time, a C × t approach. Clinical confirmation of these pharmacologic observations is evident in the therapeutic efficacy of HiDaC in patients with relapsed or SDaC-refractory acute leukemia. This is further emphasized by the significantly improved leukemia-free survival of patients with AML treated with HiDaC intensification during remission compared to those patients treated with milligram doses typical of SDaC protocols. Thus, the identification and monitoring of important parameters of drug action in tumors during the course of a clinical trial can be of substantial assistance in optimizing drug dose and schedule so as to attain the best therapeutic index.
Similar content being viewed by others
References
Gale RP: Advances in the treatment of acute myelogenous leukemia. N Engl J Med 300:1189–1199, 1979
Skipper HE, Schabel FM Jr, Wilcox WS: Experimental evaluation of potential anticancer agents. XXI. Scheduling of arabinosylcytosine to take advantage of its S-phase specificity against leukemia cells. Cancer Chemother Rep 51:125–165, 1967
Southwest Oncology Group: Cytarabine for acute leukemia in adults. Arch Intern Med 133:251–259, 1974
Rai KR, Holland JF, Glidewell OJ: Treatment of acute myelocytic leukemia: A study by Cancer and Leukemia Group B. Blood 58:1203–1212, 1981
Weil M, Glidewell OJ, Jacquillat C, Levy R, Serpick AA, Wiernik PH, Cuttner J, Hoogstraten B, Wasserman L, Ellison RR, Gailani S, Brunner K, Silver RT, Rege VB, Cooper R, Lowenstein L, Nissen NI, Haurani F, Blom J, Boiron M, Bernard J, Holland JF: Daunorubicin in the therapy of acute granulocyte leukemia. Cancer Res 330:921–928, 1973
Wiernik PH, Serpick AA: A randomized clinical trial of daunorubicin and a combination of prednisone, vincristine, 5-mercaptopurine, and methotrexate in adult non-lymphocytic leukemia. Cancer Res 32:2023–2026, 1972
Preisler HD, Davis RB, Kirshner J, Dupre E, Richards III F, Hoagland HC, Kopel S, Levy RN, Carey R, Schulman P, Gottlieb AJ, McIntyre OR, Cancer and Leukemia Group B: Comparison of three remission induction regimens and two postinduction strategies for the treatment of acute nonlymphocytic leukemia: A Cancer and Leukemia Group B study. Blood 69(5): 1441–1449, 1987
Dillmann RO, Davis RB, Green MR, Weiss RB, Gottlieb AJ, Caplan S, Kopel S, Preisler H, McIntyre OR, Schiffer C: A comparative study of two different doses of cytarabine for acute myeloid leukemia: A Phase III trial of Cancer and Leukemia Group B. Blood 78(10):2520–2526, 1991
Mayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P, Omura GA, Moore JO, Mclntyre OR, Frei III E: Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 331:896–903, 1994
Momparler RL: A model for the chemoherapy of acute leukemia with 1-B-D-arabinofuranosylcytosine. Cancer Res 34:1775–1777, 1974
Rudnick S, Cadman E, Capizzi R, Skeel R, Papac R, McIntosh S, Bertino JR: High dose cytosine arabinoside in acute leukemia. Blood 50:229, 1977
Rudnick SA, Cadman EC, Capizzi RL, Skeel RT, Bertino JR, McIntosh S: High dose cytosine arabinoside (HDARAC) in refractory acute leukemia. Cancer 44:1189–1193, 1979
Plagemann PGW, Marz R, Wohlhueter RM: Transport and metabolism of deoxycytidine and 1-B-D-arabinofuranosylcytosine into cultured Novikoff rat hepatoma cells, relationship to phosphorylation, and regulation of triphosphate synthesis. Cancer Res 38:978–989, 1978
White JC, Rathmell JP, Capizzi RL: Membrane transport influences the rate of accumulation of cytosine arabinoside in human leukemia cells. J Clin Invest 79:380–387, 1987
Wiley JS, Jones SP, Sawyer WH: Cytosine arabinoside transport by human leukemia cells. Eur J Cancer Clin Oncol 19:1067–1074, 1983
Wiley JS, Jones SP, Sawyer WH: Cytosine arabinoside influx and nucleoside transport sites in acute leukemia. J Clin Invest 69:479–489, 1982
Wiley JS, Taupin J, Jamieson GP: Cytosine arabinoside transport and metabolism in acute leukemia and T-cell lymphoblastic lymphoma. J Clin Invest 75:632–642, 1985
Capizzi RL, Oliver L, Friedman H, Davis R, Mayer R, Schiffer C, Lunghofer B, Royer G, Van Echo DA: Variations in ara-C plasma concentrations at steady-state (Cpss) during remission induction and intensification therapy of AML. A population pharmacokinetics study by CALGB. Proc Amer Soc Clin Oncol 7:57, 1988
White JC, Capizzi RL: A critical role for uridine nucleotides in the regulation of deoxycytidine kinase and the concentration dependence of 1-B-D-arabinofuranosylcytosine phosphorylation in human leukemia cells. Cancer Res 51:2559–2565, 1991
Wohlhueter RM, Plagemann PGW: The roles of transport and phosphorylation in nutrient uptake in cultured animal cells. Int Rev Cytol 64:171–240, 1980
Capizzi RL, Powell BL: Sequential high-dose ara-C and asparaginase versus high-dose ara-C alone in the treatment of patients with relapsed and refractory acute leukemias. Semin Oncol 14(suppl 1):40–50, 1987
Wolff SN, Herzig RH, Fay JW, Phillips GL, Lazarus HM, Flexner JM, Stein RS, Greer JP, Cooper B, Herzig GP: High-dose cytarabine and daunorubicin as consolidation therapy for acute myeloid leukemia in first remission: Long-term followup and results. J Clin Oncol 7(9):1260–1267, 1989
Phillips GL, Reece DE, Shepherd JD, Barnett MJ, Brown RA, Frei-Lahr DA, Klingemann H-G, Bolwell BJ, Spinelli JJ, Herzig RH, Herzig GP: High-dose cytarabine and daunorubicin induction and postremission chemotherapy for the treatment of acute myelogenous leukemia in adults. Blood 77:1429–1435, 1991
Champlin R, Gajewski J, Nimer S, Vollset S, Landaw E, Winston D, Schiller G, Ho W: Postremission chemotherapy for adults with acute myelogenous leukemia: Improved survival with high-dose cytarabine and daunorubicin consolidation treatment. J Clin Oncol 8(7):1199–1206, 1990
Schiller G, Gajewski J, Territo M, Nimer S, Lee M, Belin T, Champlin R: Long-term outcome of high-dose cytarabine-based consolidation chemotherapy for adults with acute myelogenous leukemia. Blood 80:2977–2982, 1992
Cassileth PA, Lynch E, Hines JD, Oken MM, Mazza JJ, Bennett JM, McGlave PB, Edelstein M, Harrington DP, O'Connell MJ: Varying intensity of postremission therapy in acute myeloid leukemia. Blood 79:1924–1930, 1992
Young JW, Papadopoulos EB, Cunningham I, Castro-Malaspina H, Flomenberg N, Carabasi MH, Gulati SC, Brochstein JA, Heller G, Black P, Collins NH, Shank B, Kernan NA, O'Reilly RJ: T-cell-depleted allogeneic bone marrow transplantation in adults with acute nonlymphocytic leukemia in first remission. Blood 79(12):3380–3387, 1992
Clift RA, Buckner CD, Appelbaum FR, Bearman SI, Petersen FB, Fisher LD, Anasetti C, Beatty P, Bensinger WI, Doney K, Hill RS, McDonald GB, Martin P, Sanders J, Singer J, Stewart P, Sullivan KM, Witherspoon R, Storb R, Hansen JA, Thomas ED: Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: A randomized trial of two irradiation regimens. Blood 76(9):1867–1871, 1990
Bortin MM, Horowitz MM, Rowlings PA: Progress report from the International Bone Marrow Transplant Registry. Bone Marrow Transplant 12:97–104, 1993
Gorin NC, Labopin M, Meloni G, Korbling M, Carella A, Herve P, Burnett A, Rizzoli V, Allessandrino EP, Bjorkstrand B, Ferrant A, Lowenberg B, Coser P, Simonsson B, Heibig W, Brunet Mauri S, Verdonck LF, Iriondo A, Polli E, Colombat P, Franklin IM, Souillet G, Willemze R: Autologous bone marrow transplantation for acute myeloblastic leukemia in Europe: Further evidence of the role of marrow purging by mafosfamide. Leukemia 5(10): 896–904, 1991
Schiller GJ, Nimer SD, Territo MC, Ho WG, Champlin RE, Gajewski JL: Bone marrow transplantation versus high-dose cytarabine-based consolidation chemotherapy for acute myelogenous leukemia in first remission. J Clin Oncol 10:41–46, 1992
Capizzi RL, Powell BL, Cooper MR, Stuart JJ, Muss HB, Richard II F, Jackson DV, White DR, Spurr CL, Zekan PJ, Cruz JM, Craig JB: Sequential high-dose ara-C and asparaginase in the therapy of previously treated and untreated patients with acute leukemia. Semin Oncol 12(suppl 3):105–113, 1985
Capizzi RL, Holcenberg JS: Asparaginase. In: Holland JE, Frei E (eds) Cancer Medicine. Lea and Febiger, Philadelphia, 1993, pp 796–805
Capizzi RL: The place of pharmacology in cancer medicine. Semin Oncol 4:131–133, 1977
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Capizzi, R.L. Curative chemotherapy for acute myeloid leukemia: the development of high-dose ara-C from the laboratory to bedside. Invest New Drugs 14, 249–256 (1996). https://doi.org/10.1007/BF00194527
Issue Date:
DOI: https://doi.org/10.1007/BF00194527