Association of p53 gene mutations with sensitivity to TZT-1027 in patients with clinical lung and renal carcinoma.
BACKGROUND
It has been revealed that chemotherapy using DNA-damaging agents and radiotherapy were influenced by the p53 status of tumors; however, p53 status did not influence chemotherapy using antimicrotubule agents. To elucidate whether a novel antimicrotubule agent, TZT-1027, is influenced by the p53 status of tumors, the authors investigated the sensitivities of specimens obtained from patients with nonsmall cell lung carcinoma (NSCLC) and renal cell carcinoma (RCC) to various anticancer agents, including TZT-1027, and the status of the p53 gene in those specimens.


METHODS
Twenty-nine NSCLC specimens and 22 RCC specimens were analyzed for their sensitivity to various anticancer agents and their p53 status. Sensitivities of the specimens to nine anticancer agents were determined by flow cytometric analysis. To determine p53 status, polymerase chain reaction amplification with primers for exons 5--9 was conducted, and the products were subjected to single-strand conformation polymorphism analysis.


RESULTS
In the NSCLC specimens, anticancer agents, including TZT-1027, showed strong antitumor activity against 50--75% of specimens with the wild type p53 gene. TZT-1027 showed strong antitumor activity against 40% of specimens with the mutant type p53 gene, whereas DNA-damaging agents showed such activity only in 16--28% of specimens. In RCC specimens, TZT-1027 showed potent antitumor activity in 29% of specimens with the wild type gene, and DNA-damaging agents showed such activity in 6--18% of specimens. TZT-1027 showed strong antitumor activity in 40% of specimens with the mutant type p53 gene, whereas DNA-damaging agents showed such activity only in 0--20% of specimens.


CONCLUSIONS
We found evidence to suggest that TZT-1027 was influenced less by the p53 status of specimens than DNA-damaging agents. Therefore, TZT-1027 is expected to show similar antitumor activity against tumors with a loss of p53 function as well as those with normal function of p53 in clinical fields.
Natsume
T
T
Pharmacological Research Department, Teikoku Hormone Manufacturing Company Ltd., Kanagawa, Japan. natsume-t@kw.teikoku-hormone.co.jp
Kobayashi
M
M
Fujimoto
S
S
D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics*; D004249:DNA Damage; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009842:Oligopeptides; C105791:soblidotin