Chlorodeoxyadenosine and arabinosylcytosine in patients with acute myelogenous leukemia: pharmacokinetic, pharmacodynamic, and molecular interactions

Abstract

The effectiveness of arabinosylcytosine (ara-C) for the treatment of acute myelogenous leukemia (AML) depends on the formation of its active metabolite, the triphosphate of ara-C (ara-CTP). Using biochemical modulation strategies to increase the accumulation of ara-CTP in leukemia blasts, a clinical protocol was designed combining 2- chlorodeoxyadenosine (CdA), an inhibitor of ribonucleotide reductase, and ara-C for adults with AML. The protocol stipulated an infusion of 1 g/m2 of ara-C over 2 hours on day 1. A continuous infusion of CdA (12 mg/m2/d) begun 24 hours later and continued for 5 days. Identical doses of ara-C were administered on days 3, 4, 5, and 6. Pharmacokinetic and pharmacodynamic interactions between CdA and ara-C during therapy were investigated. To complement these studies, molecular actions of the triphosphate of ara-C and CdA on DNA extension by human DNA polymerase alpha in an in vitro model system was conducted. In the circulating leukemia blasts of 7 of the 9 patients studied, ara-CTP pharmacokinetics showed a median 40% increase in the rate of ara-CTP accumulation after 24 hours of CdA infusion. The ex vivo effect of CdA on accumulation of ara-CTP in AML blasts was similar to that during therapy except that the enhancement was less. The DNA synthetic capacity of the circulating blasts was inhibited to a greater extent by administration of CdA and ara-C in combination than by either one alone. Additionally the lowered level of DNA synthesis was maintained until the next infusion of ara-C. Endogenous levels of deoxynucleotides increased 24 hours after ara-C infusion. Administration of CdA in general lowered the concentrations of all dNTPs. DNA pol alpha incorporated CdATP and ara-CTP with high affinity in a DNA primer extending over an oligonucleotide template of defined sequence. Human DNA polymerase alpha extended DNA primers terminated by CdA monophosphate (CdAMP) at its 3′-end by incorporating ara-C monophosphate (ara-CMP). The tandem incorporation of CdAMP and ara-CMP resulted in nearly complete inhibition of DNA primer extension. The insertion of two analogs in sequence, inhibition of ribonucleotide reductase, and the metabolic potentiation of ara-CTP by CdA infusion may be responsible for sustained inhibition of DNA synthesis in the circulating leukemia blasts during therapy with this combination regimen.

Influence of gemcitabine (2′,2′‐difluoro‐deoxycytidine) and 2‐chlorodeoxyadenosine on growth of normal and leukemic cellsin vitro

“…dFdC showed a close resemblance to Ara-C but with major quantitative and qualitative differences from the latter compound with regard to biological and clinical effects (1,5). Several authors have demonstrated that combined therapy consisting of 2-CdA and Ara-C was more effective than monotherapy with the drugs used separately (3,29). Our previous experiments had also con®rmed that the most effective treatment schedule was Ara-C given before 2-CdA, and that 2-CdA can potentiate the antineoplastic activity of Ara-C (30).…”

“…Ara-C is one of the most effective agents for the treatment of acute myeloid leukemias (AML). It has also been successfully applied in combined chemotherapy with purine analogs to the treatment of chronic myeloid leukemia (CML) in blast crisis (3,4). The remarkable activity of dFdC against human leukemic cell lines and solid tumors, which is more impressive than that of Ara-C, stimulated interest in clinical trials (5).…”

Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G‐CSF (CLAG‐M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group

“…A combination of FA, Ara-C, and G-CSF (FLAG regimen) has been used in the treatment of refractory and relapsed AML and poor prognosis myelodysplastic syndromes (MDS), with CR rates of between 30% and 80% reported (18)(19)(20)(21)(22). Recent studies have shown that another purine analog, cladribine (2-CdA), is also able to enhance Ara-CTP accumulation in leukemic blasts (23,24). Moreover, Chow et al reported that the combination of 2-Cda with Ara-C exhibited synergistic effect on inhibition of myeloid leukemic cell proliferation, induction of apoptosis as well as on disruption of mitochondrial membrane potential.…”

Revisiting the role of cladribine in acute myeloid leukemia: An improvement on past accomplishments or more old news?

“…The end result is cytarabine triphosphate (ara-CTP), the active form of the drug. Upon discovery that fludarabine was able to augment ara-CTP in CLL [22] and later AML [23], Gandhi et al investigated the interplay between CdA and ara-C, given CdA is a more potent ribonucleotide reductase inhibitor than fludarabine [24]. Nine patients with AML received a single dose of ara-C 1 g/m 2 on day 1 followed by CdA 12 mg/m 2 /day on days 2 to 6.…”