Mifepristone modifies the tumor microenvironment increasing the therapeutic efficiency of low doses of Doxorubicin liposomes or paclitaxel-albumin nanoparticles in a murine model of breast cancer.

SEQUEIRA GR, VANZULLI SI, LAMB CA, ROJAS PA, LANARI C.

San Antonio

Congreso; San Antonio Breast Cancer Symposium; 2012

AACR

Mifepristone modifies the tumor microenvironment increasingthe therapeutic efficiency of low doses of Doxorubicin liposomesor paclitaxel-albumin nanoparticles in a murine model of breastcancer.Sequeira GR, Vanzulli SI, Lamb CA, Rojas PA, Lanari C. Institutode Biología y Medicina Experimental, Ciudad Autónoma de BuenosAires, Argentina; Academia Nacional de Medicina, Ciudad Autónomade Buenos Aires, ArgentinaChemotherapy is the standard treatment for metastatic breast cancertoday. To overcome undesired side effects and improve drug efficacy intumor cells, different nanoparticle formulations have been developed.Paclitaxel has been bound with human albumin (Nab-paclitaxel), andpegylated liposomes have been developed for doxorubicin delivery(PEG-LD). The aim of our study was to evaluate the effect of thesetherapeutic agents in experimental mammary carcinomas expressingdifferent ratios of progesterone receptor (PR) isoforms and to evaluatethe effect of combined treatments of chemotherapeutic agents withthe antiprogestin mifepristone (MFP). Nab-paclitaxel (Abraxane,Abraxis), at a dosage of 30 and 60 mg/kg body weight administeredin three doses every four days, completely inhibited the growth of theantiprogestin-resistant C4-2-HI mouse mammary carcinoma, whichis associated with high levels of PR isoform B (PR-B) expression.C4-HI, an antiprogestin-responsive mouse tumor that shows highlevels of PR isoform A (PR-A) expression, was not inhibited bythe low Nab-paclitaxel dose. However, the combination of MFP(6 mg silastic pellet) with Nab-paclitaxel improved the efficacy ofboth single treatments. Similar experiments were conducted usingPEG-LD (Doxopeg; Laboratorios Raffo). In this case, all tumorstested (C4-HI, CC4-3-HI, 59-2-HI and C4-2-HI) were all highlyresponsive to high (18 mg/kg/week) or low (9 mg/kg/week) PEG-LDdoses. When PEG-LD concentrations were lowered to 4.5 mg/kg/week and they were combined with MFP, an improved response wasobserved with combined treatments only in tumors with high PR-Alevels (p <0.001). Using BALB/c-GFP mice, we demonstrated thatMFP treatment induced tissue remodeling in PR-A positive tumors,increasing the stromal/tumor cell ratio and the number of vessels(as shown by CD31 positive cells; p<0.001). Taking advantage ofdoxorubicin’s red autofluorescence, we showed increased levels ofdrug accumulation in tumor cells surrounding the stromal tissue.Using a human albumin antibody we demonstrated nab-paclitaxelaccumulation in similar locations. However, because increased areas(p<0.001) of stromal tissue were observed in the antiprogestin-treatedmice, the total amount of PEG-LD or Nab-paclitaxel was much higherin the combined-treated tumors. We propose that antiprogestins havethe potential to enhance the efficacy of nanotherapeutics in patientswith breast tumors with a high PR-A/PR-B ratio.