F

Like the other antimetabolites, clofarabine disrupts several pathways. It is metabolized intracellularly to its active form, the 5'-triphosphate. As the triphosphate, it inhibits NDPR, thereby decreasing cellular deoxynucleotide triphosphate pools and preventing DNA synthesis. It is also incorporated into DNA chains, but terminates chain elongations and inhibits DNA repair by inhibition of DNA polymerases.

Although activity in a preclinical model of leukemia (murine p388 cells) was successfully translated into the approved indication, the previously described issues of dosing, exposure, and adverse events profile recur for this compound as well. In the murine model, the optimal dosage was determined to be 20 mgkg_ 1, intraperitoneally q3 h x 8 on days 1, 5, and 9 of treatment.53 In the clinic, the recommended pediatric dose for ALL is 52mgm_ 2, intravenously, daily for 5 days, repeated every 2-6 weeks. However, in early clinical examinations in patients with solid tumors, the dose had to be reduced from 15 to 2mgm_ 2 due to toxicities,54 and development of the drug for the solid tumor indications was ultimately discontinued. In rodents, the half-life was estimated to be 1.84h when dosed at 25 mgkg 1, but in humans it was estimated at 5.2h at 52mgm_2. Typical cytotoxic adverse events were reported (nausea, vomiting, etc.), but cardiac and hepatic toxicity were also noted. In particular, four of 96 patients evidenced capillary leak syndrome (pleural and pericardial effusions) or systemic inflammation response syndrome, which is characterized by tachycardia, hypotension, and pulmonary edema. Clofarabine administration was discontinued for these patients.

Clofarabine is in preregistration phase for acute myelogenous leukemia (AML) in the USA, and is in trials in Europe for ALL and AML.

7.03.5.1.5 Azacitidine

The FDA approved azacitidine (13) in May 2004 as an orphan drug to be used in the treatment of myelodysplastic syndrome (MDS). MDS is a collection of bone marrow disorders in which not enough red blood cells are made. The condition may develop following treatment with drugs or radiation therapy for other diseases, and some of the forms of MDS can progress to AML. At the time of its approval, the primary treatment for MDS was supportive care in the form of blood transfusions or administration of hematopoietic factors, but no curative treatment was available for the 7000-12000 new cases diagnosed each year in the USA.56

Upjohn originally developed the compound, an N-5 aza analog of cytidine, as a cytotoxic agent over 30 years ago. As such, its enzymatic target was not known during its early development history, but it is now understood to act as a prodrug for decitabine (14). Metabolic dehydroxylation at C-2' generates 14, which is incorporated into DNA and inhibits methylation by DNA methyltransferases on cytosine polyguanine (CpG) rich regions of DNA. This inhibition is of consequence in tumor cells because they possess CpG regions which are rare in normal cells, but which must be methylated to activate signal transduction pathways resulting in cell proliferation. In the presence of decitabine, hypermethylation is shut down, slowing the cell cycle progression from S phase.57 Azacitidine is also incorporated into RNA, but very little is known about the biological effects of this.

The ORR of 15.7% for patients treated with 75-100mgm_2 of azacitidine (suspension injected subcutaneously daily for 7 days, with the cycle repeating every 4 weeks) is remarkable in light of the 0% ORR for the observation group. Patients in the observation group who crossed over into the treatment group had an ORR of 12.7%. The adverse events reported for azacitidine were those typical of cytotoxics of this type, including nausea, vomiting, and anemia.58

7.03.5.1.6 Nucleoside mimics in phase II and phase III clinical trials

Decitabine (14) is a pyrimidine nucleoside analog differing from azacitidine in that the hydroxyl group at C-2' is absent. Like cytarabine and clofarabine, which treat acute AML and ALL, decitabine is being developed as a therapy for hematological malignancies. Like azacitidine, its synthesis has been known in the literature for some time,59 but clinical trials in solid tumors were complicated by its significant marrow toxicity. Interest in it was renewed with the recognition of its inhibitory activity in DNA methyltransferases, and that reversal of hypermethylation may lead to differentiation and apoptosis in malignant cells.

Preclinical studies found activity in xenografts of breast, colon, and lung tumors in mice,33 but decitabine showed only modest clinical activity in solid tumors. Thus, ongoing focus has been on its development as a therapy for hematological malignancies. In the phase III trial for MDS, dosing with decitabine by 3h infusion of 15 mgm_2h_ 1 every 8h on 3 consecutive days every 6 weeks resulted in an ORR of 17% in the decitabine treatment arm, with 0% ORR for those receiving supportive care.60 Decitabine is in preregistration phase with the FDA for MDS, with a review date anticipated on 1 Sept 2005. Initiation of a phase III trial in AML was reported in January 2006.

Decitabine has presented challenges in its solution and metabolic stability. It decomposes rapidly in both acidic and basic solution, and significantly (7%) in 1 h at pH7 and 37 °C.61 While the mean t1/2 of azacitidine and its associated metabolites is about 4h by both intravenous and subcutaneous administration,58 the t1/2 of decitabine ranges from 7 to 35 min.62 The high clearance and total urinary excretion of < 1% indicate that decitabine is rapidly metabolized through phosphorylation and deamination.62 Further clinical experience with both azacitidine and decitabine will be required to determine which compound offers greatest benefit in MDS, ALL and AML.

Nelarabine (15) (also referred to as 506U78) is a purine nucleoside analog that is a prodrug of 9-^-d-arabinofuranosyl guanine (ara-G). Ara-G was first synthesized in 1964, but its clinical development was slowed by a difficult synthesis and poor solubility. Nelarabine is a 6-methoxy derivative that is approximately 10 times more soluble in water than ara- G,63 and is rapidly demethylated in the presence of adenosine deaminase to generate ara-G. Ara-G is cytotoxic to Tcells through accumulation and retention of its triphosphate, ara-GTP. It has been observed that patients with Tcell lymphoblasts generally have higher levels of ara-GTP than those having myeloblasts or B cell lymphoblasts. As such, nelarabine chemotherapy could be indicated for patients suffering T-cell acute lymphoblastic leukemia (T-ALL) rather than those with B cell leukemias.64

In a phase I study, the harmonic mean t1/2 over a variety of doses of nelarabine in pediatric and adult patients was found to be 14.1 min and 16.5 min, respectively, with a maximum tolerated dose (MTD) of 60 mg m _ 2 over 45-120 min intravenously daily for 5 days. Interestingly, the clearance of ara-G was higher in pediatric patients (0.312 Lh _ 1 kg_ 1) as compared with adult patients (0.213 Lh "1 kg"1), and the t1/2 of ara-G was shorter in pediatric patients as compared with adult patients (2.1 h versus 3.0 h). These studies demonstrated that nelarabine is an effective prodrug of ara-G, allowing systemic concentrations of ara-G that result in clinical activity.65 Phase II studies showed greater efficacy and lesser toxicity in pediatric than adult patients,66 and based on these Phase II studies, in October 2005 the FDA granted accelerated approval for use of nelarabine in both adults and children with T-ALL and T-cell lymphoblastic lymphoma (T-LBL) who had relapsed or not responded to two chemotherapy regimes. The principal dose-limiting side effect in pediatric patients was neurogical, with 10 of 84 patients in a phase II study reporting grade 3 or 4 events such as peripheral neuropathy (six patients). The structural similarity of nelarabine to the purine analogs fludarabine (18) and clofarabine (12) should be noted.

Thymectacin (16, NB 1011), a nucleosidephosphoramidate derivative, was designed as an enzyme catalyzed therapeutic agent (ECTA). In this strategy, the molecule acts as a substrate for an enzyme that is overexpressed in abnormal cells, such as TS. Upon reaction with the enzyme catalyst, the compound is, theoretically, released as a toxic product that can inhibit cell proliferation through interaction with other enzymes or proteins in the cell. This variation on the targeted therapy approach has the potential of having an improved therapeutic index, as the cytotoxic would be delivered in situ to the tumor. Initial studies confirm that thymectacin is indeed a substrate in vitro for TS, and is cytotoxic to tumor cell lines that overexpress TS.67 Subsequent work revealed that the product of the conversion with TS, BVdUMP (19), modifies cellular proteins, not DNA, despite the fact that it is a nucleoside analog.68 The compound is currently in phase II clinical trials for colorectal cancer.

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