Effects of novel spermine analogues on cell cycle progression and apoptosis in MALME-3M human melanoma cells.

On the basis of encouraging preclinical findings, polyamine analogues have emerged as a novel class of experimental antitumor agents. The spermine derivative N1,N11-diethylnorspermine (DE-333, also known as DENSPM) is currently undergoing Phase I clinical trials against solid tumors. A series of systematically modified DE-333 analogues differing in intra-amine carbon distances and in N-alkyl terminal substituents (i.e., methyl, ethyl, and propyl) were evaluated in MALME-3M human melanoma cells, a cell line known to be cytotoxically affected by DE-333 and especially responsive to analogue induction of the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase. Analogues accumulated to comparable intracellular concentrations and similarly affected cell growth with IC50 values in the 0.5-1.0 microM range. During prolonged incubations, diethyl and dipropyl analogues were cytotoxic, whereas two dimethyl analogues were cytostatic. Cell cycle analysis following treatment with the cytotoxic analogues revealed a prominent G1 block apparent as an accumulation of cells in G0/G1 and depletion of S-phase cells as well as a less restrictive G2 block. By contrast, cytostatic analogues incompletely arrested cells in G1, leaving a significant number of S-phase cells. Morphological and immunocytochemical analysis of detached cells revealed a far greater proportion of apoptotic cells with cytotoxic analogues than with cytostatic analogues. Although spermidine/spermine N1-acetyltransferase activity was differentially induced by the analogues, there was no obvious correlation with cell cycle effects. Overall, these data indicate a previously unrecognized combined effect of polyamine analogues on cell cycle progression and apoptosis. On the basis of structure-function relationships, these activities may be manipulated to optimize therapeutic efficacy.

A computer controlled calibrator, spectrum overlap eraser and automatic sensitivity control for an anaesthetic mass spectrometer.

The operation, design and performance of a microcomputer controlled spectrum overlap eraser and automatic sensitivity control (ASC) for a clinical mass spectrometer are described allowing calibration for up to eight anaesthetic gases in less than 15 s per gas. The critical design parameters are identified and the mathematical algorithm used discussed. Constructional details of the system are given with particular reference to the key components identified in the analysis of design parameters. The results of static and dynamic testing of the system are reported. The calibrator showed output linearities within +/- 1.7% first standard deviation (FSD) for a two part mixture of gases relevant in anaesthesia and a typical accuracy of 2.1% FSD for any point. Dynamic testing showed that the machine did not impede the overall speed of response of the system. Transient viscosity effects were adequately eliminated and ASC action effective for variation in source pressure between 11.3 X 10(-3) Pa and 2.7 X 10(-4) Pa. Mean drift with the calibrator was found to be less than 0.38% vol/vol h-1.

Detection of acoustic repetition for very long stochastic patterns.

Guttman and Julesz (1963) employed recycling frozen noise segments (RFNs) as model stimuli in their classic study of the lower limits for periodicity detection and short-term auditory memory. They reported that listeners can hear iteration of these stochastic signals effortlessly as "motorboating" for repetition periods ranging from 50 to 250 msec and as "whooshing" from 250 msec to 1 sec. Both motorboating and whooshing RFNs are global percepts encompassing the entire period, as are RFNs in the pitch range (repetition periods shorter than 50 msec). However, with continued listening to whooshing (but not motorboating) RFNs, individuals hear recurrent brief components such as clanks and thumps that are characteristic of the particular waveform. Experiment 1 of the present study describes a cross-modal cuing procedure that enables listeners to store and then recognize the recurrence of portions of frozen noise waveforms that are repeated after intervals of 10 sec or more. Experiment 2 compares the relative saliencies of different spectral regions in enabling listeners to detect repetition of these long-period patterns. Special difficulty was encountered with the 6-kHz band of RFNs, possibly due to the lack of fine-structure phase locking at this frequency range. In addition, a similarity is noted between the organizational principles operating over particular durational ranges of stochastic patterns and the characteristics of traditional hierarchical units of speech having corresponding durations.