To evaluate the utility of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a cancer therapeutic, we created leucine zipper (LZ) forms of human (hu) and murine (mu) TRAIL to promote and stabilize the formation of trimers. Both were biologically active, inducing apoptosis of both human and murine target cells in vitro with similar specific activities. In contrast to the fulminant hepatotoxicity of LZ-huCD95L in vivo, administration of either LZ-huTRAIL or LZ-muTRAIL did not seem toxic to normal tissues of mice. Finally, repeated treatments with LZ-huTRAIL actively suppressed growth of the TRAIL-sensitive human mammary adenocarcinoma cell line MDA-231 in CB.17 (SCID) mice, and histologic examination of tumors from SCID mice treated with LZ-huTRAIL demonstrated clear areas of apoptotic necrosis within 9-12 hours of injection.

This study investigated whether a polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene (C677T) modifies responses to methotrexate (MTX) in patients undergoing bone marrow transplantation. About 10% to 12% of the population carry the MTHFR TT genotype (enzyme activity, 30% of wild type [CC]). Patients (n ‫؍‬ 220) with chronic myelogenous leukemia underwent marrow allografts and were given a short course of MTX. MTX toxicity measures included the oral mucositis index (OMI), speed of engraftment (platelet and granulocyte counts), and bilirubin. Patients with lower MTHFR activity (TT genotype) had 36% higher mean OMI during days 1 to 18 (؉5.7, P ‫؍‬ .046) and 20% higher OMI between days 6 and 12 (؉3.8, P ‫؍‬ .27). Platelet counts recovered more slowly among patients with the TT genotype compared to wild type (24% slower recovery to 10 000 platelets/L, P ‫؍‬ .23; 34% slower to 20 000/ L, P ‫؍‬ .08 Folate is essential for nucleotide synthesis. The effectiveness of MTX is largely attributable to its role as an inhibitor of dihydrofolate reductase. Its metabolites also inhibit other folate enzymes, including 5,10-methylenetetrahydrofolate reductase (MTHFR), 1,3,4 which converts 5,10-methylenetetrahydrofolate to 5,10-methyltetrahydrofolate.A common MTHFR polymorphism (C677T) results in reduced activity. 5 The variant TT genotype, associated with about 30% of wild-type (CC) activity, is present in about 10% to 12% of white and Asian populations. Heterozygotes (CT) (about 60% activity) constitute approximately 40% of the population. Variations are seen in risk of acute lymphocytic leukemia, 6 colorectal neoplasia, 7-10 neural tube defects, 11,12 and possibly cardiovascular disease, 13 largely in the presence of low folate levels. Because MTX induces a low folate state, we hypothesized that toxicity would be aggravated among patients with the TT and, possibly, the CT genotype. Study design Study design and patient populationWe undertook a study of patients undergoing marrow transplantation at the Fred Hutchinson Cancer Research Center (FHCRC) from 1992 to 1999.The following criteria applied: (1) first chronic phase of chronic myelogenous leukemia 14 ; (2) first transplantation; (3) conditioning regimen: either busulfan/cyclophosphamide 15 or cyclophosphamide/total body irradiation, as described 15,16 ; (4) age at transplantation, at least 18 years; and (5) available DNA. All patients received 4 doses of MTX (intravenously, day 1, at 15 mg/m, 2 and days 3, 6, and 11, at 10 mg/m 2 ) and cyclosporine (as previously described 15 ) for prevention of GVHD. 2 All patients gave informed consent. The study was approved by the FHCRC Institutional Review Board. Data collectionData were abstracted by a single abstractor (blinded to genotypes) on previous interferon treatment, smoking, MTX administration, and, if applicable, MTX serum levels and leucovorin administration.Data from the patient database included: (1) conditioning regimen; (2) donor/matching status; (3) demographics; (4) weight, height, and calculated ...

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