Polymeric prodrugs of mitomycin C designed for tumour tropism and sustained activation

Prodrugs of mitomycin C (MMC) based on soluble poly-[N-(2-hydroxyethyl)-L-glutamine] (pHEG) polymers have been evaluated as tumour-targeted drugs. These materials are designed to exploit the enhanced permeability of tumour vasculature, combining a passive tumour tropism with decreased systemic liberation of free MMC. A tri- or tetrapeptide linkage (e.g. Gly-Phe-Ala-Leu) between pHEG and the aziridine nitrogen of MMC can combine good hydrolytic stability with rapid cleavage by lysosomal enzymes, releasing free MMC. The conjugates showed decreased systemic toxicity and could be administered to mice at a total MMC dose of 15 mg/kg i.v., compared with just 6 mg/kg for free MMC. Conjugates also showed better activity against animal models of established tumours, achieving up to 77% increased life span (ILS) against solid P388 leukaemia, compared with only 23% for free MMC, and up to 121% ILS against solid C26 colorectal carcinoma, compared with no activity for the free drug. Improving the therapeutic index of anticancer drugs by combining tumour tropism with decreased systemic toxicity is a versatile approach that should produce a new generation of improved anticancer agents.     

Prolonged tamoxifen exposure selects a breast cancer cell clone that is stable in vitro and in vivo

The effects of long-term tamoxifen exposure on cell growth and cell cycle kinetics were compared between oestrogen receptor (ER)-positive (MCF-7) and ER-negative (MDA-MB-231) cell lines. In the MCF-7 cell line, prolonged tamoxifen exposure (0.5 mumol/l for > 100 days) blocked cells in G0-G1 of the cell cycle, and slowed the doubling time of cells from 30 to 59 h. These effects corresponded to an increase in the cellular accumulation of tamoxifen over time [mean area under concentration curve (AUC) = 77.92 mumoles/10(6)/cells/day]. In contrast, in the MDA-MB-231 cell line, long-term tamoxifen exposure had no obvious effect on the doubling time, and reduced cellular tamoxifen accumulation (mean AUC = 50.50 mumoles/10(6)/cells/day) compared to the MCF-7 cells. Flow cytometric analysis of MDA-MB-231 cells demonstrated that a new tetraploid clone emerged following 56 days of tamoxifen exposure. Inoculation of the MDA-MB-231 tetraploid clone and MDA-MB-231 wildtype cells into the opposite flanks of athymic nude mice resulted in the rapid growth of tetraploid tumours. The tetraploid tumours maintained their ploidy following tamoxifen treatment for nine consecutive serial transplantations. Histological examination of the fifth transplant generation xenografts revealed that the tetraploid tumour had a 25-30 times greater mass, area of haemorrhage and necrosis, a slightly higher mitotic index and was more anaplastic than the control neoplasm. The control wildtype MDA-MB-231 tumours maintained a stable ploidy following tamoxifen treatment until the eighth and ninth transplantation, when a tetraploid population appeared, suggesting that tamoxifen treatment may select for this clone in vivo. These studies suggest that prolonged tamoxifen exposure may select for new, stable, fast growing cell clones in vitro as well as in vivo.     

The effect of solution variables on the solution of cellulose in dimethyl sulfoxide

Through the study of the effects of concentration, temperature, and molar ration (of paraformaldehyde to cellulose) on solution viscosity and per cent transmittance (at 530 nm), it has been demonstrated that cellulose solutions in dimethyl sulfoxide (DMSO) are readily produced. By heating 1, 2, and 50 to 100 parts by weight of cellulose, paraformaldehyde, and DMSO, respectively, extremely viscose cellulose solutions and gels were prepared. Solutions with concentrations as high as 10% were prepared. However, the optimum conditions to effect complete cellulose solution in DMSO at 75°C were found to be 0.5% cellulose and 0.8 and 1.0% paraformaldehyde. This corresponds to a paraformaldehyde-to-cellulose molar ratio of about 10:1.     

Strict interpretations of deterministic pushdown acceptors

Three results are established. The first is that every nondeterministic strict interpretation of a deterministic pushdown acceptor (dpda) has an equivalent, deterministic, strict interpretation. The second is that ifM ₁ andM ₂ are two compatible strict interpretations of the dpdaM, then there exist deterministic strict interpretationsM andM such thatL(M ) =L(M ₁)L(M ₂) andL(M ) =L(M ₁)L(M ₂). The third states that there is no dpda whose strict interpretations yield all the deterministic context-free languages.This author was supported in part by the National Science Foundation under Grant MCS-77-22323.     

Audience-induced inhibition of overt practice during learning.

Three experiments with 204 undergraduates examined the hypothesis that an audience can inhibit overt practice and thereby impair learning of unfamiliar words and enhance learning of familiar words. This hypothesis was derived from an analysis of motoric and symbolic mediation during learning. In comparison with learning while alone, the results show that the audience inhibited overt practice of unfamiliar and familiar words and that reduced practice was detrimental to learning unfamiliar words. Inhibition of overt practice with an audience enhanced learning of familiar words in only 1 of the experiments. Instructions to practice overtly reduced the audience-inhibition effect in learning unfamiliar words. The studies are discussed in the context of drive-theory explanations for social facilitation effects in learning. (20 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The Change of X‐ray Diffraction Peak Width During in situ Conventional Sintering of Nanoscale Powders

Diffraction peaks of nanoscale particles of 3 mol% yttria‐stabilized zirconia become sharper as the powder sinters. The reduction in the peak width is correlated with the increase in density. The sharpening of the peak agrees reasonably well with the remaining free surface area as the sample sinters. Therefore, high curvature of the free surface of the pores is assumed to lead to peak broadening (the grain boundaries that grow at the expense of the free surfaces of the pores do not have this curvature). The change in the grain size during sintering does not make a significant contribution to peak width.     

Progress in Block Copolymers

Monodisperse proteins and polydisperse carbohydrates and polyenes occur in nature. The proteins are random copolymers, but no block or graft copolymers occur in nature.     

An Elementary Introduction to the Theory of Probability

This paper describes modifications of the sequential, two-sample, grouped, rank tests developed earlier. A modified, sequential, configural rank test is discussed in some detail and is a procedure based on rerankings of observations as new groups of observations are obtained sequentially. A numerical application is given.

Monte Carlo results are presented on the modified, sequential, configural rank test and compared with earlier studies. Proofs of termination of the test are reported and outstanding unsolved problems noted.