HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Accepted manuscript (PDF) All Versions of this Article: ERC-08-0069v1 16/1/85    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Benakanakere, I. Articles by Hyder, S. Search for Related Content PubMed PubMed Citation Articles by Benakanakere, I. Articles by Hyder, S.

I Benakanakere, University of Missouri, Columbia, United States
C Besch-Williford, University of Missouri, Columbia, United States
M Ellersieck, University of Missouri, Columbia, United States
S Hyder, Department of Biomedical Science, University of Missouri - Columbia, Columbia, 65211, United States

Correspondence: Salman Hyder, Email: hyders{at}missouri.edu

Abstract

PRIMA-1 is a small molecule compound that reactivates mutant p53, restoring its normal tumor suppressor function. PRIMA-1 effectively suppresses growth of homogeneous p53-deficient tumor xenografts in immunosuppressed mice; however, the ability of PRIMA-1 to suppress growth of mammary tumors in rodents and other species is not well characterized. Here, we examined the ability of PRIMA-1 to suppress growth of DMBA-induced and progestin-accelerated DMBA-induced mammary tumors in Sprague-Dawley rats. Mammary tumors were induced in female rats with DMBA or DMBA plus progestin treatment. After tumors had reached 5-25 mm2 in size, PRIMA-1 was administered twice a day for 3 days via tail-vein injection (20 or 50 mg/kg) and tumor size was monitored for 15 days prior to sacrifice. PRIMA-1 caused regression of approximately 40% of progestin-accelerated DMBA-induced mammary tumors, but did not induce regression of native non-progestin-accelerated DMBA-induced tumors. Importantly, PRIMA-1 also suppressed the emergence of new progestin-accelerated tumors in this model. Immunological studies suggested that none of the native DMBA-induced tumors expressed mutant p53. In contrast, six of eight progestin-accelerated DMBA-induced tumors stained for mutant p53 protein. In PRIMA-1 treated tumor-bearing rats, tumor regression correlated with conversion of mutant to wild-type p53 conformation, reduced expression of VEGF and estrogen receptor, lack of blood vessel perfusion, increased expression of p21, and massively increased expression of anti-angiogenic protein SPARC. These pre-clinical results suggest that PRIMA-1, as a single agent or in combination with other anti-cancer compounds, has potential as a novel chemotherapeutic treatment for progestin-accelerated human breast cancer.