| 75-85% of lung cancers are categorized as non-small cell cancers. p53 mutations are reported in 50-60% of non-small cell lung cancers and in up to 90% of small cell tumors, thus p53 represents a common mutation in this malignancy. Preclinical studies have shown that restoring wild type p53 function leads to regression of cancers, supporting the notion of treating human cancers by way of pharmacological reactivation of p53. The novel small molecule PRIMA-1(p53-dependent reactivation and induction of massive apoptosis) has been shown to induce apoptosis in human tumor cells containing mutant p53 by restoration of the tumor suppressor function of p53. We investigated the effects of PRIMA-1 in apoptosis using human lung cancer cell lines and found that this compound could induce apoptosis in lung cancer cells containing mutant p53, but was less toxic to the cells containing wild type p53. Because most normal lung cells contain wild type p53, the PRIMA-1 is expected to be much less toxic to normal lung cells compared to cancer cells.
We have previously developed a line of lung specific mutant p53 transgenic mice, which develop spontaneous non-small cell lung cancers. Here we propose to treat these lung tumor bearing mice with PRIMA-1 either as a single agent or in combination with cisplatin. Further understanding the role of PRIMA-1 in induction of apoptosis in spontaneous lung cancer containing mutant p53 gene may lead
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