Role of apoptosis in low-dose hyper-radiosensitivity.

Little is known about the mode of cell killing associated with low-dose hyper-radiosensitivity, the radiation response that describes the enhanced sensitivity of cells to small doses of ionizing radiation. Using a technique that measures the activation of caspase 3, we have established a relationship between apoptosis detected 24 h after low-dose radiation exposure and low-dose hyper-radiosensitivity in four mammalian cell lines (T98G, U373, MR4 and 3.7 cells) and two normal human lymphoblastoid cell lines. The existence of low-dose hyper-radiosensitivity in clonogenic survival experiments was found to be associated with an elevated level of apoptosis after low-dose exposures, corroborating earlier observations (Enns et al., Mol. Cancer Res. 2, 557-566, 2004). We also show that enriching populations of MR4 and V79 cells with G(1)-phase cells, to minimize the numbers of G(2)-phase cells, abolished the enhanced low-dose apoptosis. These cell-cycle enrichment experiments strengthen the reported association between low-dose hyper-sensitivity and the radioresponse of G(2)-phase cells. These data are consistent with our current hypothesis to explain low-dose hyper-radiosensitivity, namely that the enhanced sensitivity of cells to low doses of ionizing radiation reflects the failure of ATM-dependent repair processes to fully arrest the progression of damaged G(2)-phase cells harboring unrepaired DNA breaks entering mitosis.

Qualitative metabolic fate of phenoxybenzamine in rat, dog, and man. Use of 15N-labeling.

Administration of an equimolar mixture of unlabeled and 15N-labeled phenoxybenzamine to rats and dogs facilitated identification of urinary metabolites by gas chromatography/chemical-ionization mass spectrometry by virtue of the the conspicuous equal-intensity ion pairs produced. By use of this technique N-benzyl-N-phenoxyisopropylamine (III), N-benzyl-N-(p-hydroxy-phenoxyisopropyl)amine (IV), and 2-benzylamino-1-propanol (VI) were identified as metabolites in rats. Phenoxyisopropylamine (V) as well as III and IV were identified in dogs. Compound IV was identified in humans under clinical treatment with phenoxybenzamine. The metabolites were screened for cardiovascular activity in rats. Compound III had weak alpha-adrenergic blocking activity and V elicited a hypertensive response.