Chemotherapy Dosing Schedule Influences Drug Resistance Development in Ovarian Cancer

Abstract

Drug resistance leads to chemotherapy failure and is responsible for the death of a great majority of patients with metastatic, late-stage ovarian cancer. 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 ovarian cancer. Severe combined immunodeficient mice bearing HeyA8 and HeyA8-MDR xenografts were treated with docetaxel intermittently (1Â/wk or 3Â/wk) or continuously for 21 days. Tumor mRNA expression of genes implicated in docetaxel resistance was measured by quantitative real-time-PCR. Analyzed genes included those encoding for the drug efflux transporters mdr1 and mrp7 and for molecules that interfere with or overcome the effects of docetaxel, including b-tubulinIII, actinin4, stathmin1, bcl2, rpn2, thoredoxin, and akt2. In both models, continuous docetaxel resulted in greater antitumor efficacy than 1Â/wk or 3Â/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, 3Â/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, docetaxel 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 ovarian cancer.

Effect of a high-fat diet on the hepatic expression of nuclear receptors and their target genes: relevance to drug disposition

“…Similar to our previous findings (30) , we found that rats fed a HFD (42 % energy from fat) for a period of 13 weeks had a higher weight gain and larger intra-abdominal fat mass compared with those fed a SD; however, the total lipid content in the liver did not change, as determined by biochemical and histological analysis of TAG levels in the liver (31) . This result is in agreement with previous studies showing that liver TAG levels increase during the first weeks of high fat feeding, but then gradually return to normal levels (28,31) , which suggests that there are mechanisms by which the liver adapts to increased dietary lipids (31) .…”

“…Protein extraction was performed by methods as described previously (29,30) . Briefly, 300 mg of liver tissue were band was determined with the AlphaEaseFC software (Alpha Innotech).…”

iASPP and Chemoresistance in Ovarian Cancers: Effects on Paclitaxel-Mediated Mitotic Catastrophe

“…On the other hand, recent studies showed the contribution of drug transporters as important mechanisms of chemoresistance in ovarian cancer (44,45). For example, as a primary efflux transporter, P-glycoprotein-mediated drug efflux could contribute to chemotherapy failure (45).…”

Bortezomib, carfilzomib and ixazomib do not mediate relevant transporter-based drug-drug interactions

“…As the data from the current study demonstrated that induction via PXR could be excluded, an iatrogenic increase in drug transporters, such as ABCB1, may be attributed to a selection process rather than targeted transcriptional induction. Such Darwinian selection processes leading to drug resistance have previously been described for kinase inhibitors, including imatinib (37), or for classical cytotoxic compounds like docetaxel (38).…”