Here we Vandetanib mw show that pro totypic T, B and myelogenous leukaemia lymphomas are all susceptible to DRB induced death irrespective of their p53 status. Raji cells, which were used as a prototypic example of a chemoresistant Burkitts lymphoma derived line that cannot be led to apoptosis by C2 ceramide or other antitumour agents, such as doxorubicin and etoposide, were efficiently induced to die by DRB. Moreover, the induction of apoptosis in non proliferative G0 G1 cells inherent in DRBs activity is a very attractive attribute, as quiescence is the major feature of the resistant cells that follow exposure to current chemotherapy. Finally, the evidence obtained in one AML patient of a dif ferential effect of DRB against tumour versus non malig nant cells might suggest that drug toxicity could be minimized by carefully determining the minimal effective dose.

It has been suggested that pol II inhibitors may also prove useful in the treatment of tumours with changes in DNA repair capacity and patients with chronic DNA repair deficiency syndromes such as AT and NBS, xero derma pigmentosum and Cockayne syndrome for which genotoxic treatments are strongly discouraged. The present study demonstrates that the apoptotic pathway induced by DRB is independent of ATM and NBS1, namely the proteins defective in AT and the NBS, respec tively. Thus tumours arising in these patients might be efficiently and safely treated with DRB. Moreover, ATM is frequently inactivated in sporadic cancers, particularly lymphoid malignancies. Here, too, DRB could con stitute a very convenient therapeutic option.

It could be interesting to evaluate DRB for possible clini cal applications. In comparison to other CDK inhibitors already in clinical trials, including flavopiridol and selici clib, DRB remains one of the most CDK9 selective inhib itors. CDK9 is the kinase with the most specific function limited to regulation of transcription. this selec tivity confers the ability to inhibit pol II phosphorylation rather than cell cycle CDKs or other kinases and to target noncycling cancer cells. Moreover, differently from fla vopiridol that may intercalate into the DNA thereby dam aging it, DRB does not induce DNA damage. Relatively high concentrations of DRB have been used in this work.

These could perhaps be reduced by combina AV-951 tion with other drugs if DRB were to be proposed for chemotherapy, since combination of CDK inhibitors, including DRB, with the Mdm2 antagonist, nutlin 3a, leads to the synergistic activation of the cytotoxic p53 functions and allows reduction of the concentrations of both drugs. Similar combinations could be suggested to enhance the p53 independent pathways. For example, p53 independent induction of p21Waf1 Cip1 characteris tic of histone deacetylase inhibitors resulted into enhanced cytotoxicity when combined with CDK inhibi tors.