Purine Nucleoside Analogues for the Treatment of Hematological Malignancies: Pharmacology and Clinical Applications

Abstract

The purine nucleoside analogues (PNAs), fludarabine (FA), 2-CdA (2-chlorodeoxyadenosine, 2-CdA) and pentostatin (2'-deoxycoformycin, DCF) represent a group of cytotoxic agents with high activity in lymphoid and myeloid malignancies. PNAs share similar chemical structure and mechanism of action. Several mechanisms could be responsible for their cytotoxicity both in proliferating and quiescent cells, such as inhibition of DNA synthesis, inhibition of DNA repair and accumulation of DNA strand breaks. Induction of apoptosis through the mitochondrial pathway, direct binding to apoptosome or modulation of p53 expression all lead to apoptosis, which is the main end-point of PNA action. However, individual PNAs exhibit significant differences, especially in their interaction with enzymes involved in adenosine and deoxyadenosine metabolism. Synergistic interactions between PNAs and other cytotoxic agents (alkylating agents, anthracycline antitumor antibiotics, cytarabine, monoclonal antibodies) have been demonstrated in both preclinical and clinical studies. PNAs are highly effective in chronic lymphoid leukemias and low grade B- and T-cell non-Hodgkin's lymphomas, including Waldenström's macroglobulinemia. DCF and 2-CdA are currently the drugs of choice in hairy cell leukemia. Moreover, clinical studies have confirmed the efficacy of PNAs alone or in combination protocols in the treatment of acute myeloid leukemia and myelodysplastic syndromes. Finally, PNAs, especially FA, play an important role in non-myeloablative conditioning regimens for allogenic stem cell transplantation in high-risk patients. The toxicity profiles of PNAs are similar for all agents and consist mainly of dose-limiting myelotoxicity and prolonged immunosuppression. Three other compounds: clofarabine, nelarabine and immucillin-H are currently being evaluated clinically.

Hairy Cell Leukemia: An Elusive but Treatable Disease

“…Although both cladribine and pentostatin are efficacious, the simplicity in dosing of cladribine coupled with its favorable toxicity profile, high percentage of complete remissions, and low incidence of relapse has earned it the first choice of treatment for HCL. Cladribine, like pentostatin, induces apoptosis by disrupting cellular metabolism through inhibition of DNA synthesis in both resting and dividing cells [54,55,60].…”

“…Although the purine analogues, including the newer fludarabine, share similar chemical structures and mechanisms of action, there is surprisingly little or no crossresistance among them [60,73,74]. In a study of 144 treated patients, Piro and coworkers [74] identified five patients who were either resistant to or intolerant of pentostatin.…”

“…Hematologic, neurologic, and immunologic dysfunction are the major toxicities seen with the purine analogues [60]. However, concerns about the development of second malignancies, usually occurring many years after initial treatment with interferon and nucleoside analogues, have been raised [47,48,[79][80][81][82].…”

Polyadenylation inhibition by the triphosphates of deoxyadenosine analogues

“…In particular, deoxyadenosine-based analogues such as cladribine and fludarabine ( Figure 1) have both been shown to be active against various forms of leukemias and lymphomas (reviewed in [1]). Clofarabine, a second generation chemotherapeutic agent developed following the effectiveness of fludarabine, is active against several hematological malignancies, including acute and chronic leukemias (reviewed in [2]), myelodysplastic syndromes [3], and advanced pediatric acute leukemias [4].…”

Ação do análogo de purina tóxico tubercidina em Leishmania ssp.

“…TUB é de estrutura muito similar a da adenosina (Zimmerman et al, 1978), o que possibilita sua incorporação no ácido nucléico de microrganismos e células mamíferas. Porém é responsável por vários efeitos citotóxicos, como inibição da síntese de DNA, inibição do reparo de DNA e acúmulo na fita de DNA (Robak et al, 2005).…”