Antiprogestins induce tumor vessels remodeling and increase the effects of albumin-bound paclitaxel or doxorubicin pegylated liposomes in PR-A+ but not in PR-B+ T47D xenografts.

SEQUEIRA, GONZALO; VANZULLI, SILVIA; MAY, MARÍA; ROJAS, PAOLA; LAMB, CAROLINE; MOLINOLO, ALFREDO; LANARI, CLAUDIA

San Diego

Congreso; AACR Advances in Breast Cancer Research: Genetics, Biology and Clinical Applications Conference; 2013

Chemotherapy is the standard treatment for metastatic breast cancer today. To overcome undesired side effects and improve drug efficacy in tumor cells, different nanoparticle formulations were developed. Paclitaxel was bound with human albumin (Nab-paclitaxel; Abraxane), and pegylated liposomes have been developed for doxorubicin delivery (PEG-LD; Doxopeg). We have evaluated the effect of these therapeutic agents together with antiprogestins in experimental murine mammary carcinomas (MMC) expressing different ratios of progesterone receptor (PR) isoforms and showed an increased therapeutic effect of combined treatments vs. single treatments only in tumors over expressing PR isoform A (PR-A). We showed that in these tumors antiprogestins such as Mifepristone (MFP) or Proellex, induced tissue remodeling increasing the stroma/parenchyma ratio and the number of vessels, increasing doxorubicin or Abraxane concentration within the tumors. (Sequeira et al., CTRC-AACR San Antonio Breast Cancer Symposium, December 4-8 2012). The aims of this study were: a) to characterize the tumor vessels generated during antiprogestin treatment in the MMC and b) to evaluate the effect of chemotherapeutic agents together with MFP vs. single treatments, on the growth of human T47D breast cancer cells expressing PR-A or PR isoform B (PR-B), inoculated orthotopically into NOD/LtSz-scid/IL-2Rgamma null female mice. BALB/c female mice bearing 59-2-HI (PR-A>PR-B) tumors on one flank and C4-2-HI (PR-B>PR-A) on the other flank were treated for 5 days with MFP (10 mg/kg/day). Mice were then injected with Fluorescein labeled Lycopersicon Esculentum (Tomato) Lectin (TL), or with Count Control Beads (CCB) and sacrificed after 7 min or 60 min respectively. Immunofluorescence microscopy studies showed increased TL staining (p<0.05), and vessels with increased diameter (p<0.001) in MFP-treated tumors showing higher levels of PR-A than PR-B as compared to untreated mice. Similarly, higher levels of fluorescent CCB/total number of cells were detected by flow cytometry in the same experimental groups suggesting that an increased vascular network is responsible, at least partially, of increasing the nano-chemotherapeutic drug concentration within these tumors. On the other hand, the T47D-YA and T47D-YB xenografts showed a similar responsiveness as the MMC: PEG-DL (0.9 mg/Kg/week) or Abraxane (10 mg/Kg; three doses every 4 days) combined with MFP (10 mg/Kg/Day) were more effective than the single treatments decreasing tumor size, only in the T47D-YA xenografts (p<0.05). We propose that antiprogestins have the potential to enhance the efficacy of nano-chemotherapeutic formulations in patients with breast cancer showing higher levels of PR-A than PR-B by increasing their access to the tumor cells.