mercaptopurine and mafosfamide

The meninges are a unique site of recurrence for certain malignancies because of the limited penetration of systemically administered cytotoxic drugs across the blood-brain barrier. While this phenomenon was first recognized in children with acute lymphoblastic leukemia, a similar pattern is also occurring in breast cancer, ovarian cancer, and small cell lung cancer. Recognition of the limitations of standard systemic antileukemic therapy for the treatment of meningeal disease led to the development of new therapeutic strategies targeted directly at the CNS. These include intralumbar therapy using methotrexate or cytarabine, intraventricular chemotherapy, and high-dose systemic drug administration. New agents showing promise are intrathecal diaziquone, 6-mercaptopurine, and mafosfamide.

Topics: Adolescent; Adult; Antineoplastic Agents; Aziridines; Benzoquinones; Blood-Brain Barrier; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Humans; Infant; Infant, Newborn; Leukemia; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Thiotepa

The knowledge about drug resistance in childhood leukemias and acute lymphoblastic leukemia (ALL) in general is limited. This is because of the lack of a suitable in vitro drug sensitivity assay, which is in part due to low in vitro ALL cell survival. We recently adapted the highly efficient 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay to test cells from ALL patients and showed that its results were comparable with those of the DiSC assay, up to now the most valid but laborious assay. In this study, in vitro drug sensitivity was assessed in cells from 82 children with leukemia, 79 of whom had ALL, with the MTT assay. Dose response curves were obtained for 6-mercaptopurine, 6-thioguanine (6-TG), prednisolone (Pred), daunorubicin (DNR), vincristine (VCR), cytosine arabinoside (Ara-C), L-asparaginase (L-Asp), mafosfamide, and mustine. A cytotoxic effect of methotrexate could be detected in only a few cases. Large interindividual differences in drug sensitivity were detected. Compared with leukemia cells from newly diagnosed patients, leukemia cells from relapsed patients were significantly more in vitro resistant to 6-TG, Pred, Ara-C, mafosfamide and mustine but not to DNR, VCR, and L-Asp. Improvements of culture medium and methods to increase MTT reduction were studied. From 10 components tested, addition of insulin and bovine serum albumin to serum-containing medium improved ALL cell survival. Addition of succinate did not increase the amount of MTT reduction. We conclude that the in vitro MTT assay highly facilitates large-scale studies on drug resistance of ALL patients that can lead to rational improvements in existing treatment protocols.

Topics: Asparaginase; Cells, Cultured; Child; Coloring Agents; Culture Media; Cyclophosphamide; Cytarabine; Daunorubicin; Dose-Response Relationship, Drug; Drug Resistance; Drug Screening Assays, Antitumor; Humans; Mechlorethamine; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Tetrazolium Salts; Thiazoles; Thioguanine; Vincristine