Drug resistance leads to chemotherapy failure and is responsible for the death of a great majority of @entity1 with metastatic, @entity43 . The present study addressed whether changes in the chemotherapy dosing schedule affect the development, further worsening, or circumvention of drug resistance in chemosensitive and chemoresistant @entity43 . Severe combined immunodeficient @entity19 bearing HeyA8 and HeyA8-MDR xenografts were treated with @entity1205 intermittently (1 /wk or 3 /wk) or continuously for 21 days. @entity5 mRNA expression of genes implicated in @entity1205 resistance was measured by quantitative real-time-PCR. Analyzed genes included those encoding for the drug efflux transporters @entity1262 and @entity70157 and for molecules that interfere with or overcome the effects of @entity1205 , including b-tubulinIII, @entity15168 , @entity13064 , @entity588 , @entity4114 , thoredoxin, and @entity23698 . In both models, continuous @entity1205 resulted in greater antitumor efficacy than 1 /wk or 3 /wk dosing and did not induce upregulation of any analyzed genes. Once weekly dosing caused upregulation of various drug resistance-related genes, especially in chemoresistant xenografts. More frequent, 3 /wk dosing diminished this effect, although levels of various genes were higher than for continuous chemotherapy. Drug efflux transporter expression was further examined by Western blotting, confirming that intermittent, but not continuous, @entity1205 induced significant upregulation. Overall, our results show that the presence and length of treatment-free intervals contribute to the development of drug resistance. Elimination of these intervals by continuous dosing resulted in superior antitumor efficacy and prevented drug resistance induction in chemosensitive and chemoresistant disease. These results encourage the clinical implementation of continuous chemotherapy to overcome and/or prevent drug resistance in newly diagnosed and recurrent, refractory @entity43 .

Chemotherapy dosing schedule influences drug resistance development in XXXX .

@entity1 :: ('9606', 'Species') :: ['patients'] @entity43 :: ('MESH:D010051', 'Disease') :: ['ovarian cancer', 'late-stage ovarian cancer'] @entity1262 :: ('5243', 'Gene') :: ['mdr1'] @entity588 :: ('596', 'Gene') :: ['bcl2'] @entity19 :: ('10090', 'Species') :: ['mice'] @entity5 :: ('MESH:D009369', 'Disease') :: ['Tumor'] @entity4114 :: ('6185', 'Gene') :: ['rpn2'] @entity70157 :: ('89845', 'Gene') :: ['mrp7'] @entity15168 :: ('81', 'Gene') :: ['actinin4'] @entity23698 :: ('208', 'Gene') :: ['akt2'] @entity13064 :: ('3925', 'Gene') :: ['stathmin1'] @entity1205 :: ('MESH:C067311', 'Chemical') :: ['docetaxel']
@entity43 :: (MESH:D010051,Disease) :: ['ovarian cancer']
