The spin labeled nitrosoureas 7a-e and 12 were synthesized and evaluated in vivo for their anticancer activities against the murine lymphocytic leukemia P388. Compounds 7a-c, 7e and 12 possessed activities ranging from 31 to 542 percent increase in life span (%ILS), whereas compound 7d was marginal (%ILS = 21). All CD2F1 male mice treated with the most active compounds (7a and 12) at 35 mg/kg for 9 days were alive after 30 days, whereas all mice treated with the clinical drug CCNU (1c) succumbed. Compounds 7a-e and 12 were further evaluated for their antineoplastic activity against lymphoid leukemia L 1210. Compounds 7a and 12 exhibited, on day 60, a %ILS of 713 and 620, respectively. The lipophilicities of compounds 7a-e and 12 were determined using the EPR and UV methods. Compounds 7a and 12 which differ from CCNU and MeCCNU by the replacement of the cyclohexyl and methylcyclohexyl groups with six and five membered nitroxyl radical moieties were more hydrophilic than the clinical drugs.

Animals↗

PubMedDate not supplied

Heterogeneous nuclear RNA from hairy cell leukemia patients activates 2',5'-oligoadenylate synthetase.

Interferon treatment of cells induces double-stranded RNA (dsRNA)-dependent 2',5' oligoadenylate (2-5A) synthetase, an enzyme which has been implicated in the mechanism of growth arrest in tumour cells. Since interferon (IFN) can inhibit the growth of cells that are not infected with virus, natural non-viral dsRNAs should be present in these cells which can activate 2-5A synthetase. If such nuclear dsRNAs are associated with the mechanism of growth control, cells inherently sensitive to growth inhibition by IFN should contain significant levels of 2-5A synthetase-activating dsRNAs. We measured the ability of size fractionated nuclear dsRNAs isolated from patients with hairy cell leukemia (HCL) to activate purified 2-5A synthetase. Peripheral blood mononuclear cells from HCL patients were utilized because of the inherent sensitivity of these patients to IFN treatment. The heterogeneous nuclear RNA fraction from four out of five HCL patients showed high levels of 2-5A synthetase-activating dsRNAs. The 2-5A formed contained biologically active trimers, tetramers, pentamers and hexamers as demonstrated by HPLC analysis and their ability to activate RNase L. In contrast, the nuclear RNA fraction from three out of four healthy controls were unable to activate 2-5A synthetase. These results indicate that natural, nuclear dsRNAs inherently exist in IFN-sensitive cells and imply that these molecules may play a role in the inhibition of cellular growth.

2',5'-Oligoadenylate Synthetase↗

PubMedDate not supplied

Progressive supranuclear palsy presenting with psychiatric features.

A patient with progressive supranuclear palsy who presented with psychiatric features is reported. His case illustrates the difficulty of early diagnosis of this condition. Associated psychiatric symptoms are common and may precede the occurrence of gaze palsy. Our patient's behavioural problems responded to fluoxetine.

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