Activity of liposomal taxol against breast cancer cells / by Melanie Heney.

Abstract

Taxol (paclitaxel) is one of the most effective chemotherapeutic agents used for the treatment of multiple cancers, including breast, ovarian, and, non-small-cell lung cancer. However, development of taxol resistance with prolonged use is common, requiring the use of the chemotherapeutic agent in combination with other treatments. In addition to the development of resistance, taxol is difficult to administer due to its high lipophilicity, and it requires solubilization with Cremophor EL (polyethoxylated castor oil) and ethanol, which often lead to adverse side-effects, including life-threatening anaphylaxis. Incorporation of taxol in DPPC:DMPG (dimyristoyl phosphatidylcholine: dimyristoyl phosphatidylglycerol) liposomes may not only eliminate the adverse reactions associated with the Cremophor EL vehicle, but also decrease other toxicities that arise from the drug's action in non-targeted tissues. Moreover, liposomally-encapsulated taxol might have the potential to overcome resistance by facilitating the cellular delivery of taxol at the site of action. Liposomes have been shown to be very effective in the delivery of other chemotherapeutic agents, such as adriamycin. This project deals with the use of liposomes as a novel delivery method for taxol. The effectiveness of liposomally-encapsulated taxol, as well as its ability to overcome taxolresistance, was tested on MCF-7 breast cancer cells and A549 lung cancer cells. It was also tested for its ability to overcome taxol-resistance in two taxol-resistant MCF-7 cell lines. The results of our studies demonstrated the following: i) the lipid components of the liposomal formulation were non-toxic; ii) the liposomally-encapsulated taxol was more effective than conventional taxol in increasing the susceptibility of MCF-7 and taxol-resistant MCF-7 breast cancer cells as well as A549 lung cancer cells to taxol (as determined by MTT cytotoxicity assays, DNA laddering, flow cytometry, and determination of mitotic indexes); and, iii) the improved effectiveness of taxol delivered as a liposomal formulation was associated with higher intracellular levels of the chemotherapeutic agent in cancer cells (determined by Ultra-Performance Liquid chromatographic technique). The results of these studies indicate that liposomes may be potentially used as a novel method for the delivery of taxol in cancer chemotherapy.