Troxacitabine69 (17) is a pyrimidine nucleoside analog possessing two unique structural features: L-configuration at the C-4' carbon and replacement of the C-3' ring carbon with oxygen, resulting in a dioxolane ring. It is active as its triphosphate metabolite and inhibits DNA polymerases. However, due to the inversion of configuration at C-4', it is not a substrate for deoxycytidine deaminase, unlike other pyrimidine nucleoside analogs such as cytarabine and gemcitabine. In addition, unlike cytarabine and gemcitabine, radiolabeling studies show that the major route of cellular uptake is passive diffusion. Consequently, it may be active in patients who are refractory to cytarabine and gemcitabine when resistance is linked to active transport mechanisms.

This compound also demonstrates significant PK differences between rats and humans. In rats, the PK was independent of dosage concentration, the elimination t1/2 is 1.65h and its clearance is 1.38Lh_ 1kg_ 1 (single dose at 10, 25, or 50 mgkg_ 1 administered intravenously or orally).70 After 5 days of treatment in humans, (intravenous infusion over 30 min, daily x 5 at 0.12-1.8mgm_2) the t1/2 was found to be 39h and clearance was 127mLmin_ 1.71 The longer t1/2 relative to other nucleoside analogs is attributed to its inactivity in deoxycytidine deaminase, so the drug is not cleared rapidly.

Troxacitabine was investigated in phase I trials in patients with either solid or hematological malignancies. Phase II investigations were completed in a variety of leukemias including AML and ALL, and in pancreatic cancer. Advances in delivery of nucleoside mimics

The activity of capecitabine in colorectal cancer demonstrates an effective strategy to enhance the activity of nucleoside mimics: increase the exposure of the active drug by delivery as a prodrug. Other delivery strategies have been effective as well, including formulations of drug in liposomes, in implanted microspheres, or in polysaccharides.

DepoCyt is an injectable, sustained release form of cytarabine (ara-C; 9), for the treatment of antineoplastic meningitis (NM) arising from lymphoma (lymphomatous meningitis).72 Ara-C acts by inhibiting DNA polymerase as well as through incorporation of its triphosphate into DNA. A phase III trial of DepoCyt in lymphomatous NM showed it to be more convenient and associated with a higher positive response rate than ara-C. The DepoCyt formulation of ara-C is encapsulated in the aqueous chambers of a spherical 20-mm matrix comprising of lipids biochemically similar to normal human cell membranes (phospholipids, triglycerides, and cholesterol). When injected into the cerebrospinal fluid (CSF) at room temperature, the particles spread throughout the neuroaxis and slowly release ara-C. A single injection of free unencapsulated ara-C maintains cytotoxic concentrations in the CSF for <24h,73 whereas a single injection of 50 mg of DepoCyt maintains cytotoxic concentrations of ara-C in most patients in the CSF for > 14 days.74 As cytotoxicity is a function of both drug concentration and duration of exposure, this formulation maintains high concentrations of ara-C in the cancer cell for prolonged periods of time and increases the efficacy of the agent.

5-FU has been investigated in implanted microspheres for treatment of brain tumors (glioblastoma).75 The microspheres are biodegradable poly(lactide-co-glycolide) with a mean size of 40 mm and drug loading of 21.6%+ 1.3%. The microspheres allow for controlled release of 5-FU into the tumor due to a combination of diffusion and degradation. In this indication, 5-FU acts as a local radiosensitizer, improving the efficacy of radiation therapy. Phase I

results from a 10 patient trial showed an overall survival time of 40 weeks, and 5-FU was detected at very low levels (0-25 ngmL_ 1) in the blood and CSF of some, but not all, patients. The results were sufficiently encouraging for a phase II study to be conducted, and the results are pending analysis.

Release of 5-FU from a polysaccharide matrix is currently under phase I investigation in DAVANAT (1,4-^-d-galactomannan). The rationale for this delivery system is threefold. First, sugars on the tumor cells can differ from those of normal cells, allowing for tumor-cell specific delivery of drug. In addition, galactoside-containing carbohydrates disturb cell association, thus preventing new tumor cells from adhering to host tissue, and disrupting metastasis. Lastly, entrapment of hydrophobic drugs can improve their solubility and distribution to the target tumors. DAVANAT is a soluble polysaccharide, derived from plant sources, which is co-administered with 5-FU by intravenous injection. In preclinical studies, coadministration of DAVANAT with 5-FU in mouse xenografts of C0L0205 and HT-29 tumors resulted in a decrease of median tumor volume and increase in mean survival time.76 Interim analysis of five of six cohorts in the phase I study showed mean exposure parameters of AUC and Cmax increased with repeated doses of 5-FU and with escalating doses of DAVANAT.77 Details regarding the compound have not been widely disclosed in peer-reviewed literature, and thus the full promise of the strategy remains to be understood. Antifolates

The biosynthesis of nucleic acid precursors depends on folate metabolism. Tetrahydrofolate, along with its cofactors, are the main carriers of one carbon units in the synthesis of thymidine and purine nucleosides. Agents interfering with the metabolism of folate are termed antifolates, and can be divided into three general subtypes. Classical antifolates are generally highly polar molecules that are actively transported by the RFC and in some cases the MFR. They are also substrates for FPGS and exert much of their effects through polyglutamates. Antifolates that are not substrates for FPGS have been termed nonclassical antifolates, and can be broken into two further subgroups, type A and type B. The type A nonclassical antifolate is generally a more lipophilic drug that is passively transported and does not utilize the RFC. The type B antifolate can be thought of as a hybrid between the classical and nonclassical antifolates. While still being nonpolyglutamatable like their type A counterparts, type B antifolates are generally polar, water-soluble inhibitors that utilize the RFC for cell entry. Type B antifolates typically cannot form polyglutamates because the gamma-carboxyl of the glutamic acid moiety has been blocked or otherwise modified.78

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