Nucleoside Analogs in Cancer Therapy

Bruce D. Cheson, Michael J. Keating, William Plunkett, Bruce D. Cheson, Michael J. Keating, William Plunkett

• Editorial: CRC Press
• Año: 2021
• ISBN:
  9781000148664
• Edición: 1
• Categoría: Medicina
• Categoría: Teoría, práctica y referencia médicas

Offering the most current and complete coverage of nucleoside analog activity in oncology and hematology, this single-source volume includes topics from pharmacology to previously unpublished clinical findings on the pivotal role of fludarabine, cladribine, and pentostatin in the management of diseases, such as chronic lymphocytic and hairy cell leukemia, non-Hodgkin's lymphoma, membranous nephropathy, and rheumatoid and psoriatic arthritis.

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Nucleoside Analogs: Cellular Pharmacology, Mechanisms of Action, and Strategies for Combination Therapy

William Plunkett and Varsha Gandhi

The University of Texas M. D. Anderson Cancer Center, Houston, Texas

I. INTRODUCTION

Classically, the therapeutic paradigm of killing a growing population of cancer cells supported strategies aimed at limiting the ability of these cells to replicate their DNA. Exploitation of new knowledge of the biochemical pathways that supplied deoxynucleotides resulted in the development of several functional groups of clinically useful antimetabolites that today comprise a major class of therapeutically active compounds in the treatment of cancer. Their general action is ultimately to interfere with DNA synthesis. This has been achieved by several different mechanistic strategies that are readily categorized.

Thymidylate synthase inhibitors block the production of thymidylate and thereby deprive cells of dTTP needed for DNA synthesis. The lead compound of this group is 5-fluorouracil, although several newer antimetabolites of reduced folates also inhibit the enzyme. Antifols are represented classically by methotrexate, which generally blocks production of reduced folate cofactors that are required by de novo pathways of deoxynucleotide synthesis. Some of the newer compounds inhibit multiple enzymes required for reduced folate synthesis, but in each case the de novo pathway of purine nucleotide synthesis is inhibited.

Nucleoside analogs compose the last major group of antimetabolites currently in clinical use. After entry into the cell and phosphorylation by deoxynucleoside salvage pathways, it is generally the triphosphate of these compounds that is the active metabolite. The triphosphates, acting in a mechanism-based fashion, become incorporated into DNA and interfere with the continued elongation of DNA during replication and repair of DNA damage. Although the clinical activities of analogs such as cytarabine and the mercaptopurines have been restricted to hematologic malignancies, newer compounds such as fludarabine, cladribine, and, more recently, gemcitabine exhibit additional metabolic properties and multiple mechanisms of action.

Because no nucleoside analog has been demonstrated to be curative in any malignancy when used alone, it is essential to develop rationales for optimizing their use in combinations. To that end, the initial approach of this chapter will be to compare and evaluate the metabolic and pharmacodynamic characteristics of anticancer nucleoside analogs of major importance. Subsequently, our objective is to use an understanding of the pharmacology and mechanisms of action of the nucleosides as rationales for the design of combinations with other anticancer drugs or modalities such as radiation. In the end, we believe that such therapeutic strategies promise to extend the clinical activities of the individual nucleosides more broadly through the hematologic malignancies and into the effective treatment of solid tumors.

The chemical structures of nucleosides to be reviewed in this chapter are shown in Fig. 1. Cytarabine (1-β-D-arabinosylcytosine, ara C) is one of the most thoroughly studied drugs in cancer chemotherapy (1). It derives its cytotoxic properties from the arabinosyl carbohydrate moiety, which is metabolized along the pathways of deoxycytidine and its nucleotides. Although without activity in solid tumors, cytarabine is active in many hematologic malignancies; it is used predominantly to treat adult acute myelogenous leukemia. The success of cytarabine inspired the synthesis and evaluation of other arabinosyl analogs. Vidarabine (arabinosyladenine) was ineffective as an intravenous drug, largely because of its susceptibility to rapid metabolic clearance by deamination by the ubiquitous adenosine deaminase. As an approach to the second generation of arabinosyladenine compounds, placement of a fluorine atom at the 2 carbon of the adenine ring caused electronic changes that made the amino group resistant to deaminative hydrolysis (2). The resulting arabinosyl compound, 9-β-D-arabinosyl-2-fluoroadenine, an analog of deoxyadenosine, was shown to have biological activity (3). The clinical formulation of fludarabine was completed by addition of a phosphate group at the 5′ carbon of this compound, which increased its solubility by more than 100-fold. The initial clinical activity of fludarabine was demonstrated in chronic lymphocytic leukemia (4), but it is appreciated that fludarabine was wide-spectrum activity in many indolent lymphocytic diseases (5). Substitution of the 2 carbon of deoxyadenosine with chlorine to produce cladribine also protected the compound from deamination (6). Although cladribine was shown to have activity against hairy cell leukemia (7), subsequent investigations have demonstrated that this drug is effective in many indolent B-cell diseases (8,9). Gemcitabine is another analog of deoxycytidine, taking its cytotoxic activity from the two fluorines placed in the geminal configuration on the 2 carbon (10). The fact that gemcitabine has impressive activity in a variety of solid tumors distinguishes it from the foregoing nucleoside analogs (11).

Figure 1 Structures of nucleoside analogs used in cancer therapy.

II. CELLULAR PHARMACOLOGY OF NUCLEOSIDE ANALOGS

All nucleoside analogs require phosphorylation to a nucleotide form, generally the triphosphate, to be biologically active. An overview of the metabolism of these compounds will provide a context for appreciating strategies for exploiting pharmacologic differences among the analogs. Table 1 provides a summary of the parameters that are reviewed in this section.

A. Transport into Cells

Specific nucleoside transport systems provide the major pathway for nucleoside analogs to cross the plasma membrane and gain access to cells (12,13). These appear to rely predominantly on facilitated transport mechanisms, although energy-dependent active transport systems have been described. As many as five nucleoside transport systems have been distinguished on the basis of physiologic characteristics (13), and studies of the cloneing of the responsible genes are now being reported.

Table 1 Metabolic Characteristics of Nucleoside Analogs

Characteristic	Cytarabine	Fludarabine	Cladribine	Gemcitabine
Transport	Yes	Yes	Yes	Yes
Catabolite	ara-U^a	None known	ClAde^b	dFdU^c
Deoxycytidine kinase Km. μM	10	200–400	5	2
Rate-limiting step	Deoxycytidine kinase	Deoxycytidine kinase	Monophosphate kinase	Deoxycytidine kinase
Active metabolite	Triphosphate	Triphosphate	Triphosphate	Diphosphate, triphosphate

^aArabinosyluracil.

^b2-Chloroadenine.

^c2′,2′-Difluorodeoxyuridine.

Cellular transport appears to be a high-capacity, low-affinity (K_m) process that is not likely to be saturable at therapeutically achievable nucleoside concentrations (14,15). Although detailed comparative studies are needed, the available evidence does not suggest major differences in the transport mechanisms utilized among the nucleosides for entry into tumor cells. There is experimental evidence indicating that at low concentrations of nucleoside in plasma, the absolute number of transporters on a leukemia cell may be limiting to nucleoside uptake and subsequent triphosphate formation (14,15). Because transport is bidirectional, effective inhibitors of nucleoside transporters may be used in therapeutic strategies either to block the efflux of cellular nucleoside analogs (16), or to limit the influx of normal nucleotides that would compete with an antimetabolite that is already in the cell (17).

B. Catabolism

Mechanisms of clearance distinguish the purine and pyrimidine nucleoside analogs. Cytarabine and gemcitabine are cleared metabolically by deamination by cytidine deaminase (19,20), an enzyme found at high specific activities in large body organs such as liver, spleen, and kidneys. This is largely due to the first-pass clearance that rapidly eliminates the parent nucleosides with a half-life of between 10 and 20 min (1,21). At initial concentrations of cytarabine (>100 μM) generated by high-dose regimens, nonlinear elimination kinetics have been observed that could be fitted to two- or three-compartment models (22,23,24). Neither of the deamination products of cytarabine and gemcitabine, arabinosyluracil and difluorodeoxyuridine, respectively, appear to be further catabolized. Studies in experimental systems have provided no indication that these metabolites have therapeutic activity of their own. Nevertheless, there are indications that the relatively high concentrations of arabinosyluracil may somehow effect cell cycle progression and thereby augment the activity of cytarabine (25). In contrast, there is very little metabolism of the purine nucleoside analogs, and as a result clearance of fludarabine and cladribine occurs mainly by renal excretion (26,27). Thi...