PMID: 8958179Jan 1, 1996Paper

Curative chemotherapy for acute myeloid leukemia: the development of high-dose ara-C from the laboratory to bedside

Investigational New Drugs
R L Capizzi

Abstract

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 x t) resulted in a palliative therapeutic outcome. In marked contrast, exposure to lower doses for a protracted period (c x T) was curative. Clinical use of ara-C in patients with AML patterned after the murine experience, c x 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 tr...Continue Reading

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Citations

Nov 8, 2012·International Journal of Hematology·Brian McLaughlinMichael Boyiadzis
Feb 8, 2011·Journal of Biomaterials Science. Polymer Edition·Sumit MehrotraChristina Chan
Jun 19, 2004·Neurotoxicology and Teratology·Hirofumi YamauchiKunio Doi
Apr 8, 2015·PloS One·Costa BachasJacqueline Cloos
Feb 1, 2010·Indian Journal of Medical Sciences·Thomas S KuruvillaZevita Furtado

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