Influence of O6-benzylguanine on the anti-tumour activity and normal tissue toxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea and molecular combinations of 5-fluorouracil and 2-chloroethyl-1-nitrosourea in mice

Previous studies have demonstrated that novel molecular combinations of 5-fluorouracil (5FU) and 2-chloroethyl-1-nitrosourea (CNU) have good preclinical activity and may exert less myelotoxicity than the clinically used nitrosoureas such as 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). This study examined the effect of O6-alkylguanine-DNA-alkyltransferase (ATase) depletion by the pseudosubstrate O6-benzylguanine (BG) on the anti-tumour activity and normal tissue toxicity in mice of three such molecular combinations, in comparison with BCNU. When used as single agents at their maximum tolerated dose, all three novel compounds produced a significant growth retardation of BCNU-resistant murine colon and human breast xenografts. This in vivo anti-tumour effect was potentiated by BG, but was accompanied by severe myelotoxicity as judged by spleen colony forming assays. However, while tumour resistance to BCNU was overcome using BG, this was at the expense of enhanced bone marrow, gut and liver toxicity. Therefore, although this ATase-depletion approach resulted in improved anti-tumour activity for all three 5-FU:CNU molecular combinations, the potentiated toxicities in already dose-limiting tissues indicate that these types of agents offer no therapeutic advantage over BCNU when they are used together with BG. © 1999 Cancer Research Campaig

Dimensional and Cosmological Co-Expansion through Dynamic Dimensionality

<p>Postulate: the Cosmological Scale Factor in a Universe with fundamentally dynamic dimensionality, is proportional to dimensional co-expansion described by a radical expression, Df root Dr, where Dr is the number of sequentially revealed spatial dimensions (three in our present Universe) and Df is the remainder of furled extra dimensions where the total dimensionality of revealed plus furled dimensions is constant. An illustration of this proportionality is presented for a Universe with a total of nine or ten spatial dimensions, which exhibits characteristics of early inflation, intermediate decelerating expansion, nearly linear expansion and late accelerating expansion.</p

Simple empirical functions for the observed densities of matter, dark matter and dark energy

<p>Particularly elegant and very compact empirical functions closely approximating the ESA Planck CMB measurements of the densities of matter, dark matter and dark energy have been discovered and are presented here as a possible stimulus for further investigation.</p

It from Qutrit graphics

<div>Graphics relate to</div><div>It from Qutrit: Braided Loop Metaheuristic</div