Drug-targeting in combined cancer chemotherapy: tumor growth inhibition in mice by association of paclitaxel and etoposide with a cholesterol-rich nanoemulsion.
BACKGROUND
Lipid nanoemulsions (LDE) may be used as carriers of paclitaxel (PTX) and etoposide (ETP) to decrease toxicity and increase the therapeutic action of those drugs. The current study investigates the combined chemotherapy with PTX and ETP associated with LDE.


METHODS
Four groups of 10-20 B16F10 melanoma-bearing mice were treated with LDE-PTX and LDE-ETP in combination (LDE-PTX + ETP), commercial PTX and ETP in combination (PTX + ETP), single LDE-PTX, and single LDE-ETP. PTX and ETX doses were 9 μmol/kg administered in three intraperitoneal injections on three alternate days. In two control groups mice were treated with saline solution or LDE alone. Tumor growth, metastasis presence, cell-cycle distribution, blood cell counts and histological data were analyzed. Toxicity of all treatments was evaluated in mice without tumors.


RESULTS
Tumor growth inhibition was similarly strong in all treatment groups. However, there was a greater reduction in the number of animals bearing metastases in the LDE-PTX + ETP group (30 %) in comparison to the PTX + ETP group (82 %, p < 0.05). Reduction of cellular density, blood vessels and increase of collagen fibers in tumor tissues were observed in the LDE-PTX + ETP group but not in the PTX + ETP group, and in both groups reduced melanoma-related anemia and thrombocytosis were observed. Flow cytometric analysis suggested that LDE-PTX + ETP exhibited greater selectivity to neoplastic cells than PTX-ETP, showing arrest (65 %) in the G(2)/M phase of the cell cycle (p < 0.001). Toxicity manifested by weight loss and myelosuppression was markedly milder in the LDE-PTX + ETP than in the PTX + ETP group.


CONCLUSIONS
LDE-PTX + ETP combined drug-targeting therapy showed markedly superior anti-cancer properties and reduced toxicity compared to PTX + ETP.
Lipid Metabolism Laboratory, the Heart Institute (INCOR) of the Medical School Hospital, University of São Paulo, São Paulo, Brazil.
Iara F
IF
Kretzer
Durvanei A
DA
Maria
Raul C
RC
Maranhão
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D008078:Cholesterol, LDL / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods*; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005217:Fat Emulsions, Intravenous / Q000627:therapeutic use*; D005260:Female; D005434:Flow Cytometry; D007274:Injections, Intraperitoneal; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000627:therapeutic use*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects
D008078:Cholesterol, LDL; D005217:Fat Emulsions, Intravenous; D005047:Etoposide; D017239:Paclitaxel