Key result
LCFL-PTX/DXR matches free drug antitumor efficacy while eliminating cardiotoxicity.
Why the study?
The combination of paclitaxel and doxorubicin for breast cancer management presents cardiotoxic synergism due to pharmacokinetic interactions, and strategies to minimize this toxicity are needed.
Does a liposomal formulation co-encapsulating paclitaxel and doxorubicin improve antitumor activity and reduce cardiac toxicity compared to free drug combinations in a murine breast cancer model?
Does a liposomal formulation co-encapsulating paclitaxel and doxorubicin improve antitumor activity and reduce cardiac toxicity compared to free drug combinations in a murine breast cancer model?
Absolute Event Rate: 66.52% vs 66.87%
p-value: p=>0.05
Co-encapsulating paclitaxel and doxorubicin in long-circulating and fusogenic liposomes maintains antitumor efficacy while preventing the synergistic cardiotoxicity seen with their free co-administration in a murine model.
Extending DXR-PTX interval may attenuate cardiotoxicity in rats; leaves open whether findings translate to clinical breast cancer regimens.
To associate paclitaxel (PTX) with doxorubicin (DXR) is one of the main chemotherapy strategies for breast cancer (BC) management. Despite the high response rates for this combination, it presents a cardiotoxic synergism, attributed to pharmacokinetic interactions between PTX and both DXR and its metabolite, doxorubicinol. One of the main strategies to minimize the cardiotoxicity of the combination is to extend the interval of time between DXR and PTX administration. However, it has been previously suggested that their co-administration leads to better efficacy compared to their sequential administration. In the present study, we investigated different molar ratio combinations of PTX:DXR (10:1; 1:1, and 1:10) against the 4T1 murine breast cancer cell line and concluded that there is no benefit of enhancing PTX concentration above that of DXR on the combination. Therefore, we obtained a long-circulating and fusogenic liposomal formulation co-encapsulating PTX and DXR (LCFL-PTX/DXR) at a molar ratio of 1:10, respectively, which maintained the in vitro biological activity of the combination. This formulation was investigated for its antitumor activity and toxicity in Balb/c mice bearing 4T1 breast tumor, and compared to treatments with free PTX, free DXR, and the mixture of free PTX:DXR at 1:10 molar ratio. The higher tumor inhibition ratios were observed for the treatments with free and co-encapsulated PTX:DXR in liposomes (66.87 and 66.52%, respectively, P>0.05) as compared to the control. The great advantage of the treatment with LCFL-PTX/DXR was its improved cardiac toxicity profile. While degeneration was observed in the hearts of all animals treated with the free PTX:DXR combination, no signs of cardiac toxicity were observed for animals treated with the LCFL-PTX/DXR. Thus, LCFL-PTX/DXR enables the co-administration of PTX and DXR, and might be considered valuable for breast cancer management.
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Franco et al. (2018) studied Murine breast cancer. Long-circulating and fusogenic liposomes co-encapsulating paclitaxel and doxorubicin (LCFL-PTX/DXR) vs. Free PTX, free DXR, mixture of free PTX:DXR, and control was evaluated on Tumor inhibition ratio (p=>0.05). LCFL-PTX/DXR yielded a tumor inhibition ratio of 66.52% (similar to free PTX:DXR at 66.87%, P>0.05) but eliminated the cardiac toxicity observed with the free combination.