Mutant p53-dependent growth suppression distinguishes PRIMA-1 from known anticancer drugs: a statistical analysis of information in the National Cancer Institute database.
We recently identified PRIMA-1 as a low molecular weight compound that restores tumor suppressor function to mutant p53 proteins and has anti-tumor activity in vivo (1). Here we report the statistical analysis of the effect of PRIMA-1 on a panel of human tumor cell lines using information available in a database at the Developmental Therapeutics Program of the National Cancer Institute (NCI). We extracted growth inhibition profiles for PRIMA-1 and 44 known anticancer agents, p53 status of cell lines, population doubling time, and level of p53 protein expression from the NCI database. The data were analyzed by linear regression, Wilcoxon matched pairs test, and cluster analysis. In a subset of human cell lines derived from colon, ovarian, renal, and non-small cell lung cancer and melanoma, the level of mutant p53 expression correlated with cell population doubling time, r = -0.53, P = 0.018. The GI(50) values for PRIMA-1 correlated with levels of mutant p53, r = -0.75, P = 0.0002. PRIMA-1 showed a statistically significant preference at P = 0.04 for growth inhibition of tumor cell lines expressing mutant p53 as compared with lines expressing wild-type p53. In contrast, none of several known anticancer drugs showed such preference. PRIMA-1 inhibited the growth of cell lines derived from various human tumor types in a mutant p53-dependent manner. This distinguishes PRIMA-1 from known anticancer drugs and supports the idea that PRIMA-1 can serve as a lead for the development of novel therapeutic compounds.
Bykov
Vladimir J N
VJ
Karolinska Institutet, Department of Oncology-Pathology, Cancer Center Karolinska (CCK), R8:04 Karolinska Hospital, SE-171 76 Stockholm, Sweden.
Issaeva
Natalia
N
Selivanova
Galina
G
Wiman
Klas G
KG
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001372:Aza Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002455:Cell Division; D016000:Cluster Analysis; D019992:Databases as Topic; D004791:Enzyme Inhibitors; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D016014:Linear Models; D009154:Mutation; D009316:National Institutes of Health (U.S.); D013997:Time Factors; D014407:Tumor Cells, Cultured; D014481:United States
D000970:Antineoplastic Agents; D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; C451219:2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one