Mutations in p53 are common events during carcinogenesis and have been suggested to affect sensitivity to chemotherapy. Recently, the common polymorphism at codon 72, resulting in either an arginine (72R) or proline (72P) residue, was shown to differentially affect the response to anticancer drugs. Here, we have generated isogenic lung cancer cell lines to evaluate the effect of six p53 hotspot mutations (R175H, G245S, R248W, R249S, R273H, and R282W) in conjunction with the codon 72 polymorphism, for their response to a variety of anticancer drugs, either alone or in combination. The data indicate that 72R mutations do not confer general resistance to cisplatin, etoposide, gemcitabine, vinblastine, and taxol. For doxorubicin, cells expressing 249-72R were more resistant than the 249-72P cells. Combined treatment with cisplatin + etoposide resulted in an additive effect in cells expressing most 72R and 72P mutations, except for the 175-72R cells which were refractory to combined treatment. However, combined treatment with cisplatin + gemcitabine resulted in the absence of an additive effect in cells expressing the 273-72R and 282-72R mutants, unlike their 72P counterparts. Nonetheless, all p53 mutants (72R or 72P) equally inhibited p73-mediated transcriptional activity in lung cancer cells, suggesting that the selective resistance conferred by some 72R mutants to certain drugs is probably due to other p73-independent effects of these mutants. Together, the data show that the status of codon 72 polymorphism and p53 mutations can be used as a means for prediction of treatment response, although variables for each cancer type requires detailed evaluation.p53 is arguably the most critical tumor suppressor gene and mutations in the p53 gene are considered to represent the most common genetic alterations in human cancer (1 -3). About 90% of the p53 mutations are found in the central DNA-binding domain of p53 (1, 3). These mutations therefore affect the DNA-binding activity of p53, leading to the loss of p53-mediated transcriptional activation and hence, p53 functions such as apoptosis, and cell cycle arrest and repair (1,2). Besides the gene mutations, several reports have focused on p53 polymorphisms as risk factors for malignant disease. A polymorphic site at codon 72 in exon 4 encodes either an arginine amino acid (Arg 72R ) or a proline residue (Pro 72P ;. This polymorphism is located in a proline-rich region of the p53 protein that is required for the growth suppression and apoptosis mediated by p53 but not for cell cycle arrest (7 -9). The two polymorphic variants of wild-type p53 have been shown to have some differences in biochemical properties such as differential binding to components of the transcriptional machinery (10). Moreover, it has also been suggested that the 72R variant is much more susceptible to degradation by the human papillomavirus E6 protein (11) and recent analysis has shown that the 72R variant is more efficient in inducing cell death than the 72P variant in some cell types (12,13)...