Response and Toxicity to Cytarabine Therapy in Leukemia and Lymphoma: From Dose Puzzle to Pharmacogenomic Biomarkers

Abstract

Cytarabine is a pyrimidine nucleoside analog, commonly used in multiagent chemotherapy regimens for the treatment of leukemia and lymphoma, as well as for neoplastic meningitis. Ara-C-based chemotherapy regimens can induce a suboptimal clinical outcome in a fraction of patients. Several studies suggest that the individual variability in clinical response to Leukemia & Lymphoma treatments among patients, underlying either Ara-C mechanism resistance or toxicity, appears to be associated with the intracellular accumulation and retention of Ara-CTP due to genetic variants related to metabolic enzymes. Herein, we reported (a) the latest Pharmacogenomics biomarkers associated with the response to cytarabine and (b) the new drug formulations with optimized pharmacokinetics. The purpose of this review is to provide readers with detailed and comprehensive information on the effects of Ara-C-based therapies, from biological to clinical practice, maintaining high the interest of both researcher and clinical hematologist. This review could help clinicians in predicting the response to cytarabine-based treatments.

Keywords: Ara-C; mechanism of resistance; pharmacogenetics; target therapy.

Figure 1

As with other nucleoside analogues and their physiologic counterparts, cytarabine enters cells via nucleoside transport proteins, the most important one being the equilibrative inhibitor-sensitive (es) receptor (ABC). Once inside the cell, cytarabine requires activation for its cytotoxic effects. The first metabolic step is the conversion of cytarabine to cytarabine monophosphate by the enzyme deoxycytidine kinase (DCK). Cytarabine is subsequently phosphorylated to cytarabine diphosphate and cytarabine triphosphate, respectively. Cytarabine triphosphate is a potent inhibitor of DNA polymerases, which, in turn, interferes with DNA chain elongation, DNA synthesis, and DNA repair. In addition, cytarabine is incorporated directly into DNA and functions as a DNA chain terminator, interfering with chain elongation. Catabolism of cytarabine involves two key enzymes, cytidine deaminase (CDA) and deoxycytidyne monophosphate deaminase (DCMD). These breakdown enzymes convert cytarabine and cytarabine monophosphate into the inactive metabolites, uracil arabinoside and arabinosyluracil monophosphate, respectively. Other catabolic enzymes that may affect cytarabine metabolism include pyrophosphatase, 5-nucleotidase. The balance between intracellular activation and degradation is critical in determining the amount of drug that is ultimately converted to cytarabine triphosphate and, thus, its subsequent cytotoxic and antitumor activity.