Cancer research
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9,10-Anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazol-2-yl)hydrazone] dihydrochloride (CL 216942; bisantrene hydrochloride; NSC 337766), a member of a new chemical class of compounds with antineoplastic properties, has been evaluated for antitumor activity in experimental murine tumor systems. The compound produced significant increases in life span (LS) and long-term survivors among mice bearing transplantable leukemias and solid tumors. Optimal treatment regimens resulted in an ILS of greater than 173 and 151% in mice with P388 and L1210 leukemia, respectively, an ILS of greater than 85% in mice with Lieberman plasma cell tumor, and an ILS of greater than 200, 150, and 63%, respectively, in mice with B16 melanoma, colon tumor 26, and Ridgway osteogenic sarcoma. ⋯ CL 216942 was a potent inhibitor of DNA and RNA synthesis in L5178Y lymphoma cells cultured in vitro, and preliminary studies indicated the drug was a DNA-intercalating agent. The drug was cytotoxic for rapidly proliferating and nonproliferating (G0) human colon carcinoma WiDR cells in vitro. U
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Six renal transplant recipients with abnormal lymphoproliferative disorders were studied in an attempt to define their clinical features and the role of Epstein-Barr virus (EBV) in their pathogenesis. Patients were either teenage (three) or in the sixth decade (three). The younger patients presented an average of 3 months after transplantation with fever, sore throat, and lymphadenopathy; had been markedly immunosuppressed; frequently had preceding or concomitant cytomegalovirus infections; and two of three had a rapidly fatal course. ⋯ Impaired host defenses allow the EBV-transformed B-lymphocytes to escape normal control mechanisms. This impairment is invariable and influenced by many factors resulting in the observed spectrum of disease. Cytogenetic changes, however, may also be important.
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The nature of the inhibition of Ehrlich tumor cell ribonucleotide reductase by combinations of agents directed at the non-heme iron-containing component and the effector-binding component was studied with the use of isobolograms. From these studies, it was determined that the combinations of pyrazoloimidazole (IMPY) and dialdehyde of inosine, IMPY and deoxyguanosine triphosphate (dGTP), IMPY and deoxyadenosine triphosphate (dATP), and IMPY and deoxythymidine triphosphate (dTTP) gave synergistic inhibition of cytidine diphosphate reductase. ⋯ The combinations of hydroxyurea and IMPY, 4-methyl-5-aminoisoquinoline thiosemicarbazone (MAIQ) and IMPY, and dialdehyde of inosine and dialdehyde derivative of 5'-deoxyinosine gave antagonistic inhibition. Other combinations utilizing MAIQ and dATP, MAIQ and dGTP, MAIQ and dTTP, hydroxyurea and dGTP, and hydroxyurea and dTTP gave inhibition which was additive.
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We have studied repair of ultraviolet light (UV)-induced damage in a strain of Bloom's syndrome cells which we have shown to be defective in host cell reactivation of UV-irradiated herpes simplex virus. Excision repair was monitored by following loss of sensitivity of DNA in permeabilized cells to digestion by the Micrococcus luteus UV endonuclease preparation. The Bloom's syndrome fibroblasts apparently removed endonuclease-sensitive sites from the DNA slightly less efficiently than did normal strains. ⋯ We were therefore able to detect only minor defects in the repair of UV-induced damage in Bloom's syndrome fibroblasts. This is consistent with the normal survival exhibited by these cells. The defect in excision repair may, however, be sufficient to allow the cellular repair capacity to become saturated at high infecting multiplicities of UV-irradiated herpes simplex virus.
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Pools of deoxyribonucleoside triphosphates in L1210 cells were assayed for drug-induced changes that might indicate the metabolic basis for retention of 1-beta-D-arabinofuranosylcytosine triphosphate by these cells after treatment with methotrexate (MTX) and 1-beta-D-arabinofuranosylcytosine (ara-C). Within 20 min after treatment with MTX, the pool of deoxythymidine triphosphate (dTTP) had decreased by about 50% and during the next 8 hr decreased slowly to 30% of its initial level. When MTX-induced decreases in the cellular contents of deoxycytidine triphosphate (dCTP), deoxyadenosine triphosphate (dATP), and deoxyguanosine triphosphate (dGTP) were normalized to percentages of the initial levels, they coincided with the second slower phase of decrease in dTTP. ⋯ When ara-C and MTX were administered together, levels of dTTP, dATP, and dGTP did not change significantly, and the increase in dCTP was only 25% of the increase after treatment with ara-C alone. Thus, the most striking change in deoxyribonucleoside triphosphate pools after combined administration of MTX and ara-C was an increase in dCTP concentration that reached about one-fourth the concentration achieved with ara-C alone. We suggest that MTX, by attenuating the ara-C-induced increase in dCTP, caused a change in the allosteric regulation of either deoxycytidine kinase or deoxycytidylate deaminase (or both), thereby potentiating the activity of ara-C.