We studied the consequences of interfering with DNA topoisomerase IIalpha (topo IIalpha) activity on melphalan-induced @entity137 . In order to accomplish our goal we used three different approaches to interfere with topo IIalpha. These include: i) use of three V79 @entity3569 lung fibroblast-derived mutant cell lines, V507, V511, and V513 that are dysfunctional in topo IIalpha activity; ii) treatment of cells with @entity2879 ( @entity2879 ) which inhibits topo IIalpha through the formation of DNA-enzyme cleavable complex; and iii) exposure of cells to @entity6843 or @entity10976 (Zinecard) that inhibits the activity of topo IIalpha by restricting its access to DNA. Based on clonogenic survival assays, all three approaches resulted in a significant potentiation of @entity137 of melphalan suggesting that topo IIalpha plays an important role in processing of DNA damage induced by @entity3601 . Furthermore, using alkaline elution assay, we show that melphalan-induced DNA cross-link formation and its repair is faster in V511 cells compared to the parental V79 cells. However, melphalan-induced @entity3731 ( @entity3731 ) are found to be significantly higher in V511 cells compared to V79 cells. In addition, we find an excellent correlation between melphalan-induced @entity3731 and @entity137 . These results could be explained on the assumption that topo IIalpha plays an important role in damage processing through excision repair of melphalan-induced DNA cross-links. However, in the absence of topo IIalpha the damages are primarily processed by recombination repair which may be prone to deleterious genetic alterations resulting in increased lethality as the frequency of recombination increases. In summary, our results demonstrate that: i) topo @entity942 is associated with increased sensitivity to melphalan; ii) deficiency of topo IIalpha is associated with an increase in melphalan-induced @entity3731 ; iii) increase in melphalan-induced @entity3731 is associated with an increase in @entity137 ; and iv) downregulation of topo IIalpha may be a useful approach to modulate the @entity137 of melphalan in combination chemotherapy regimens. These results have several important clinical implications. First, interference with topo IIalpha using agents such as @entity2879 or @entity10976 may provide a useful approach to enhance the efficacy of melphalan in combination chemotherapy regimens. Second, @entity5 which develop resistance to topo IIalpha-directed drugs due to quantitative or qualitative alterations in topo IIalpha may show increased susceptibility to a chemotherapy regimen containing melphalan.

Interference with topoisomerase IIalpha potentiates melphalan XXXX .

@entity137 :: ('MESH:D064420', 'Disease') :: ['cytotoxicity'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumors'] @entity6843 :: ('MESH:C045459', 'Chemical') :: ['merbarone'] @entity2879 :: ('MESH:D005047', 'Chemical') :: ['etoposide', 'VP-16'] @entity3601 :: ('MESH:D008558', 'Chemical') :: ['melphalan'] @entity3731 :: ('MESH:D058288', 'Disease') :: ['SCE', 'sister chromatid exchanges'] @entity3569 :: ('10029', 'Species') :: ['Chinese hamster'] @entity942 :: ('MESH:D003677', 'Disease') :: ['IIalpha deficiency'] @entity10976 :: ('MESH:D011929', 'Chemical') :: ['ICRF-187']
@entity137 :: (MESH:D064420,Disease) :: ['cytotoxicity']
