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This Article Full Text Full Text (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 Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Benakanakere, I. Articles by Hyder, S. M Search for Related Content PubMed PubMed Citation Articles by Benakanakere, I. Articles by Hyder, S. M

Department of Biomedical Sciences, Dalton Cardiovascular Research Center, University of Missouri, 134 Research Park Drive, Columbia, Missouri 65211, USA¹ Veterinary Pathobiology, University of Missouri, Columbia, Missouri, USA² Agriculture Experiment Station, University of Missouri, Columbia, Missouri, USA

(Correspondence should be addressed to S M Hyder; Email: hyders{at}missouri.edu)

p53 Reactivation and induction of massive apoptosis (PRIMA-1) is a small-molecule compound that reactivates mutant p53, restoring its normal tumor suppressor function. PRIMA-1 effectively suppresses the growth of homogeneous p53-deficient tumor xenografts in immunosuppressed mice; however, the ability of PRIMA-1 to suppress the growth of mammary tumors in rodents and other species is not well characterized. Here, we examined the ability of PRIMA-1 to suppress the growth of 7,12-dimethylbenz[a]anthracene (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). Tumor size was monitored every day following PRIMA-1 for at least 15 days prior to killing. PRIMA-1 caused regression of 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 any new progestin-accelerated tumors in this model. Immunological studies with an antibody that selectively reacts with mutant p53 suggested that none of the native DMBA-induced tumors expressed mutant p53. By contrast, six out 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 vascular endothelial growth factor and estrogen receptor, lack of blood vessel perfusion, increased expression of p21, and massively increased expression of anti-angiogenic protein, secreted protein acidic and rich in cysteine. 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.