When administered at doses of 30C200 mg/m2, Cmax varies between 0.1C30 g/ml and is reached after the mean time of Cefprozil hydrate (Cefzil) 29.6 min (5,8). at least partly mediated through nucleoside transporters, suggesting its purine analogue-like properties. On the other hand, Arimany-Nardi (14) found no interaction of bendamustine with hCNT and hENT proteins, known to mediate the uptake of purine and pyrimidine drug analogs, suggesting a lack of their role in cellular uptake of the drug and emphasizing the importance of human organic cation transporter 1. The role of organic transporters was further corroborated by the finding that renal human organic anion transporter 3 increases the susceptibility of lymphoma cells to bendamustine uptake (15). Schw?nen (16) first reported efficacy of bendamustine alone or in combination with fludarabine in inducing Rabbit Polyclonal to FGFR1/2 (phospho-Tyr463/466) apoptosis in B-cell chronic lymphocytic leukemia (CLL) cells (16). Notably, apoptosis is not the only mechanism of bendamustine-mediated cytotoxic effects, since it causes an alternative mechanism called mitotic catastrophe that bypasses apoptosis which is often impaired in tumor cells (11). Normally, when DNA damage or DNA replication stress occurs, these changes are detected by check points that arrest the cell cycle at either the G1-S (G1 check point) or the G2-M (G2 check point) transition to prevent the accumulation and propagation of genetic errors during cell division and to allow DNA repair to take place (9,17). Occurrence of damaged DNA in form of double-strand breaks (DSBs) triggers ataxia telangiectasia-mutated (ATM) check point protein kinase and downstream targets, protein kinase called checkpoint kinase (Chk)2 and transcription factor p53, most important for prevention of cells to enter S phase (9,17). Due to the repair mechanism of DSBs or due to replication stress which arises during S phase, single-strand breaks are generated and ataxia telangiectasia and Rad3-related protein and Chk1 signaling pathways are activated. If no DNA repair is achieved, cells do not enter mitosis but undergo apoptotic cell death or senescence, often by TP53-dependent mechanisms (9,17). In the case of mitotic catastrophe, if for example, TP53 is mutated, there is an insufficient G2 check point regulation and cells enter mitosis with significant DNA damage followed by apoptosis, necrosis and senescence (17,18). Gene expression profiling studies conducted by Leoni (10) demonstrated bendamustine-mediated inhibition of expression of genes involved in DNA repair and mitotic checkpoints indicating that the assumed intercalation of the drug into the DNA and downregulation of check point inhibitors could be the mechanism behind mitotic catastrophe. Different experimental models have shown different effects of Cefprozil hydrate (Cefzil) bendamustine on the cell cycle. The drug causes significantly more T-cell lymphoma cells to be arrested in the S-phase than chlorambucil or phosphoramide (10), and similar effect was observed in both MM (19,20) and MCL cell lines (21). However, in different experimental models, bendamustine induced ATM-Chk2-Cdc2-mediated arrest in G2 phase of the cell cycle of MM cells and p53-mediated apoptosis, the latter augmented by inhibition of p38 MAPK (22). In human DLBCL cell lines, the drug Cefprozil hydrate (Cefzil) increased the proportion of cells in G2-M and bendamustine-induced activation of the ATM pathway and accumulation of surviving cells at G2-M phase was inhibited by surviving suppressant (23). An explanation of these findings may come from studies on HeLa cells suggesting a dose-dependent effect on cell cycle checkpoints and DNA repair (24). Low concentrations of bendamustine transiently arrested cells in G2, which then entered mitosis and divided normally, while a 4-fold higher concentration Cefprozil hydrate (Cefzil) arrested cells in S phase resulting in aberrant mitosis and cell death (24). Proposed mechanism of action of bendamustine is shown in Fig. 2. Open in a separate window Figure 2. Potential mechanism of action of bendamustine. The figure was created with BioRender.com. 3.?Bendamustine-pharmacokinetics Pharmacokinetics of bendamustine has been studied, in addition to humans, in mice, rats and dogs. The extent of binding and formation of metabolites is different among species, but while some authors considered this to be clinically relevant (5), others suggested that the few new metabolic products detected in the human mass balance study that had not been observed in rats, largely represent adducts that are formed by reaction of bendamustine with endogenous compounds in the urine and conclude that the metabolic elimination of bendamustine is qualitatively the same in humans and rats (25,26). Although the pharmacokinetics of multiple-dose administration of the drug have not been investigated, there is a significant correlation between.