Despite intensive remedies including temozolomide (TMZ) administration, glioblastoma patient prognosis remains dismal and innovative therapeutic strategies are urgently needed. efficacy defined as maximum difference between damage in tumor and healthy cells was reached for extracellular pH between 6.8 and 7.5. Next, TMZ PK\PD in a solid tumor was demonstrated to highly depend on its spatial configuration as spread cancer cells or fragmented tumors presented higher TMZ\induced damage as compared to compact tumor spheroid. Simulations highlighted that smaller tumors were less acidic than bigger ones allowing for faster TMZ activation and their closer distance to blood capillaries allowed for better drug penetration. For model parameters corresponding to U87 glioma cells, inter\cell variability in TMZ uptake play no role regarding the mean drug\induced damage in the whole cell population whereas this quantity was increased by inter\cell variability in TMZ efflux which was thus a disadvantage in terms of drug resistance. Overall, this study revealed pH as a new potential target to significantly improve TMZ antitumor efficacy. and are respectively the volumes and pH values of the extra\ and intracellular compartments, and are TMZ efflux and uptake rate constants, respectively, and so are the pH\reliant price constants of TMZ change into MTIC and following MTIC activation in to the cation C, may be the cation degradation price continuous which presents a higher reactivity, and may be the DNA\adduct development price constant. As with Ballesta et?al.,4 and so are modeled the following: region. Each tumor cell can take up one part of the grid with measurements is defined as cm2/s may be the TMZ diffusion coefficient20 and may be the level of the extracellular moderate (Appendix?A). TMZ transportation into/from the cells just happens at spatial area occupied by cells. The intracellular concentrations of TMZ ((because of the limited creation price of H+ from the cells), the pH can be computed the following: may Lurbinectedin be the pH in regular healthy cells (ie, oxygenated tissue normally, corresponding to may be the lower pH level within tumors which may be only 6.5.28, 29 We set both of these values to pHand pHrespectively. and (Appendix?Shape?A2). 2.3.2. Intracellular pH One hallmark from the tumor cells can be their capability to survive within an acidic environment Lurbinectedin C that they donate to generate C by keeping their Lurbinectedin intracellular pH at physiological amounts. Alternatively, this acidic environment is detrimental to normal cells that have not acquire this ability.28 Intracellular pH regulation is a complex process that is not completely elucidated yet.30, 31 However, simultaneous measurements of extra and intracellular pH were made in several tumor cell types that all exhibit the reversed pH property where the intracellular pH is higher than the extracellular one.30, 32, 33, 34 For this study, we needed to evaluate the intracellular pH given the extracellular one. To that end, we compiled from the literature intra and extracellular measurements performed on different cell types that were available for a wide range Lurbinectedin of extracellular pH. The different points obtained from four different studies, corresponding to four different tumor cell types: mice mammary carcinoma (SCK),34 Chinese hamster lung fibroblasts (CC139),33 human pancreatic carcinoma (PANC\1),32 general tumor cells30 could be fitted by linear regression Rabbit Polyclonal to KCNK15 to calculate the coefficients to give the pHrelationship for tumor cells (Figure?3, and for normal and tumor cells. The function corresponds to normal cells and is derived from the physiological status point (sandglass point). We consider that as indicated by the function.39 Since normal cells are not able to survive acidity, the function is only valid from under this value we consider that the intracellular acidity is lethal to the cell. The function is a linear regression estimated from the points corresponding to different tumor cell types: SCK cells (bullets),34 CC139 cells (squares),33 PANC\1 cells (triangles),32 other tumor cells (diamonds). The dotted line indicates where = for normal cells (Figure?3, with an acidic shift. As a result, the amount of DNA\adducts in the.