mercaptopurine and Neuroblastoma

The antimetabolite 6-mercaptopurine (6-MP) is an important component in the treatment of specific cancer subtypes, however, the development of drug resistance and dose-limiting toxicities can limit its effectiveness. The therapeutic activity of 6-MP requires cellular uptake, enzymatic conversion to thio-GMP and incorporation of thio-GTP into RNA and DNA, as well as inhibition of de novo purine synthesis by methyl-thio-IMP. Mechanisms that prevent 6-MP entry into the cell, prevent 6-MP metabolism or deplete thiopurine intermediates, can all lead to 6-MP resistance. We previously conducted a high-throughput screen for inhibitors of the multidrug transporter MRP4 using 6-MP sensitivity as the readout. In addition to MRP4-specific inhibitors, we identified a compound, CCI52, that sensitized cell lines to 6-MP independent of this transporter. CCI52 and its more stable analogue CCI52-14 also function as effective chemosensitizers in vivo, substantially extending survival in a transgenic mouse cancer model treated with 6-MP. Chemosensitization was associated with an increase in thio-IMP, suggesting that CCI52 functions directly on 6-MP uptake or metabolism. In addition to its chemosensitizing effects, CCI52 and CCI52-14 inhibited the growth of MYCN-amplified high-risk neuroblastoma cell lines and delayed tumor progression in a MYCN-driven, transgenic mouse model of neuroblastoma. These multifunctional inhibitors may be useful for the further development of anticancer agents and as tools to better understand 6-MP metabolism.

Topics: Animals; Antimetabolites, Antineoplastic; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Mercaptopurine; Mice; Mice, Transgenic; Molecular Structure; N-Myc Proto-Oncogene Protein; Neoplasms, Experimental; Neuroblastoma; Thiazoles

A 29-year-old pregnant woman diagnosed with acute lymphocytic leukemia maintained remission with daily cyclophosphamide and intermittent prednisone treatment. She delivered a male twin with multiple congenital abnormalities who was diagnosed with papillary thyroid cancer at 11 years of age and stage III neuroblastoma at 14 years of age. The female twin was unaffected and has exhibited normal development to date. First trimester exposure to cyclophosphamide has been associated with major malformations. Metabolites of cyclophosphamide have been demonstrated to be teratogens and carcinogens in animals. Differences in placental or fetal hepatic cytochrome P-450 may account for the variability in response between the twins. In addition, disparity between the twins may be the result of differences in metabolite inactivating enzymes present either in fetal liver or placenta. The risk of second malignancies caused by alkylating agents such as cyclophosphamide has been well documented in adults and children but to the best of our knowledge this is the first description of transplacental second cancer.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Adrenal Gland Neoplasms; Adult; Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Papillary; Cyclophosphamide; Diseases in Twins; Female; Humans; Infant, Newborn; Male; Maternal-Fetal Exchange; Mercaptopurine; Neuroblastoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Pregnancy; Pregnancy Complications, Neoplastic; Prenatal Exposure Delayed Effects; Thyroid Neoplasms; Time Factors; Twins, Dizygotic; Vincristine

Topics: Cell Line; Cells, Cultured; Drug Resistance; Floxuridine; Glioma; Humans; Mercaptopurine; Morphine Dependence; Neoplasms, Experimental; Nervous System Diseases; Neuroblastoma; Neurophysiology; Thioguanine; Vasoactive Intestinal Peptide

Topics: Bone Neoplasms; Child, Preschool; Cyclophosphamide; Female; Ganglioneuroma; Humans; Infant; Mercaptopurine; Neoplasm Metastasis; Neuroblastoma; Prednisone; Skin Neoplasms; Vincristine

In an effort to propose more effective chemotherapeutic regimens for the treatment of neuroblastoma, we have characterized mouse, neuroblastoma variants whose growth in tisue culture are resistant to antimetabolites. We report the partial characterization of two lines resistant to 6-mercaptopurine (6-MP). Concentrations of drug required to inhibit their growth rates 50% are 110- and 575-fold higher, respectively, than that inhibiting the sensitive parental clone. Unlike most 6-MP-resistant cell lines described previously, both neuroblastoma populations display normal activities of hypoxanthine-guanine phosphoribosyltransferase but greatly reduced accumulation of 14-C-labeled 6-MP. Drug accumulation was inhibited by adenine, blocked by dinitrophenol but not ouabain and strongly temperature dependent suggesting a need for cytoplasmic phosphoribosylation. Possible mechanisms for this reduction in 6-MP retention are discussed. Importantly, eight clones isolated in 6-MP-free media from the 110-fold resistant population of cells demonstrated quantitatively identical growth inhibition at all drug concentrations tested suggesting that the original 110-fold resistant neuroblastoma population was homogenous with respect to its mechanisms of resistance.

Topics: Animals; Cell Line; Drug Resistance; Hypoxanthine Phosphoribosyltransferase; Mercaptopurine; Mice; Neuroblastoma; Tetrahydrofolate Dehydrogenase; Time Factors

Topics: Acetyltransferases; Animals; Bromodeoxyuridine; Carbon Radioisotopes; Catechol O-Methyltransferase; Cattle; Cell Differentiation; Cell Survival; Cell Transformation, Neoplastic; Cells, Cultured; Choline; Clone Cells; Enzyme Activation; Humans; Mercaptopurine; Mice; Neuroblastoma; Purines; Thioguanine; Time Factors; Tritium; Tyrosine 3-Monooxygenase

Topics: Aminopterin; Child; Child, Preschool; Diagnosis, Differential; Haptoglobins; Hematologic Diseases; Humans; Infant; Infections; Leukemia; Lymphoma; Mercaptopurine; Neuroblastoma; Prednisone

Topics: Adrenal Cortex Hormones; Antimetabolites; Antineoplastic Agents; Child; Hodgkin Disease; Humans; Infant; Leukemia; Lymphatic Metastasis; Mercaptopurine; Methotrexate; Neoplasm Metastasis; Neoplasms; Neuroblastoma; Nitrogen Mustard Compounds; Toxicology; Vincristine

Topics: Antineoplastic Agents; Busulfan; Child; Cyclophosphamide; Dactinomycin; Humans; Hydroxyurea; Leukemia; Leukemia, Lymphoid; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Mercaptopurine; Neoplasms; Neuroblastoma; Sarcoma; Urea