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

Numerical models of faulting at oblique spreading centers

Obliquely spreading mid-ocean ridges, such as the Reykjanes Ridge, display two distinct fault sets distinguishable by orientation and position: on-axis faults are oriented oblique to both the trend of the axis and the normal to the relative plate separation vector, while faults on the flanks strike approximately parallel to the ridge axis. Numerical modeling techniques are used here to simulate the development of faulting on the Reykjanes Ridge. Stresses acting in a cross section through the lithosphere at a slow spreading ridge are investigated using the fast Lagrangian analysis of continua (FLAC) explicit difference modeling software. The predicted stresses from the cross-sectional models are imposed as a condition in boundary element models of fracture propagation and linkage. On-axis fault simulations run under conditions similar to the Reykjanes Ridge successfully reproduce the mapped distribution of faults and predict the observed orientation of the axial volcanic ridges. Simulations of fractures away from the axis show the development of axis-parallel faults by the interaction and linkage of fractures which have been rafted off-axis, also in accord with observations. Stresses modeled in cross section favor downdip displacement on faults dipping toward the ridge axis