Extended Exposure Topotecan Significantly Improves Long-Term Drug Sensitivity by Decreasing Malignant Cell...

Area of Science:

• Oncology
• Pharmacology
• Cancer Biology

Background:

• Maximum tolerable dosing (MTD) is the standard for aggressive cancers but has limitations.
• Alternative dosing strategies, like extended exposure (EE), offer improved toxicity and novel mechanisms.
• Preventing drug resistance is crucial for sustained cancer treatment efficacy.

Purpose of the Study:

• To investigate if extended exposure (EE) topotecan can enhance long-term drug sensitivity by preventing resistance in prostate cancer.
• To compare the efficacy and resistance profiles of EE topotecan versus MTD topotecan.
• To elucidate underlying phenotypic changes using transcriptomic analysis.

Main Methods:

• Utilized a spheroidal model system of castration-resistant prostate cancer.
• Administered extended exposure (EE) and maximum tolerable dosing (MTD) of topotecan.
• Employed transcriptomic analysis to assess phenotypic alterations.

Main Results:

• EE topotecan exhibited a significantly higher barrier to resistance than MTD topotecan.
• EE topotecan maintained consistent efficacy over the study period (IC50 54.4 nM at Week 6).
• MTD topotecan induced epithelial-mesenchymal transition (EMT), upregulated efflux pumps, and altered topoisomerases.

Conclusions:

• EE topotecan provides a more sustained treatment response for castration-resistant prostate cancer.
• EE topotecan preserves a less aggressive malignant phenotype compared to MTD.
• Extended exposure dosing is a promising strategy for overcoming topotecan resistance.