Dependence of chemotherapy response on p53 mutation status in a panel of human cancer lines maintained in nude mice

Abstract

In contrast to findings in vitro, the clinical response to anticancer chemotherapy is not simply associated with the p53 mutation status. To analyze the relationship between the actual response of solid tumors with p53 mutation and other biological characteristics, we used a human cancer-nude mouse panel of 21 lines derived from stomach, colorectal, breast, lung, and liver cancers for experimental chemotherapy. We examined the tumor growth rates of the cancer lines and the effects of nine drugs in clinical use, namely, mitomycin C (MMC), cisplatin (CDDP), nimustine hydrochloride (ACNU), irinotecan (CPT-11), cyclophosphamide (CPA), 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207), a 4:1 mixture of uracil and FT-207 (UFT), 5′ ′ ′ ′-deoxy-5-fluorouridine (5′ ′ ′ ′-DFUR), and adriamycin (ADM), on these tumors. The chemotherapy response was expressed as the tumor growth inhibition rate (IR). The genomic DNA sequences of the p53 gene in exons 5 through 8 were analyzed in these cancer tissues, and p53 mutations were detected in 10 of the 21 cancer lines (48%). Resistance to MMC was observed in p53 mutant tumors with smaller IRs than those for wild-type tumors (57.7% vs. 79.9%, P < < < <0.03). No significant differences were noted with the other eight drugs. To explore the role of the p53 function in the chemotherapy response, we calculated the correlation coefficients between chemosensitivity and tumor growth rate separately in p53 mutant and wild-type groups. In the p53 wild-type group, we found a positive correlation for the following drugs: ADM (P < < < <0.02), ACNU (P < < < <0.007), CPA (P < < < <0.011), UFT (P < < < <0.012), and FT-207 (P < < < <0.02). In the p53 mutant group, only CPA (P < < < <0.003) showed a positive correlation. The kinetics suggests that in the wild-type tumors, DNA damage caused by anticancer drugs occurs proportionally to the rate of DNA synthesis, and p53-mediated apoptosis is subsequently induced. The low frequency of positive correlation in the p53 mutant tumors is compatible with the loss of function or malfunction of mutant p53. The present results provide kinetic evidence that p53 function affects the response to anticancer drugs. Preserved p53 function tended to confer good chemosensitivity on rapidly growing tumors. However, the p53 mutation status did not seem to be suitable for use as an exclusive indicator to predict the chemotherapy response of human cancer xenografts. (Cancer Sci 2004; 95: 541-546) he biological, biochemical, and genomic characteristics of individual cancer tissues have been studied to predict the clinical course and response of such tissues to radiological and chemotherapeutic treatment. [1][2][3][4] In vitro studies with cultured cell lines are convenient means of evaluating the response to various agents. 5) However, the in vivo response to chemotherapeutic treatment can not be determined simply on the basis of the response of cancer cells in vitro.6, 7) To predict more accurately the in vivo response to anticancer drugs, we established a preclinical secondary...

Equivalent effect of DNA damage-induced apoptotic cell death or long-term cell cycle arrest on colon carcinoma cell proliferation and tumour growth

“…This is in agreement with the increasing amount of data showing that apoptosis may not be the main mechanism of response of cancer cells to treatment (Brown and Attardi, 2005). This hypothesis is consistent with the observed lack of correlation between the response/nonresponse to DNA-damaging agents and the p53 status (Jansen et al, 1997;Jacob et al, 2001;Koike et al, 2004), and may explain the controversy concerning the p53 status as a prognostic factor (Liu and Gelmann, 2002). Indeed, the longest delay of exponential tumour growth after treatment was observed in HCT116Chr3 cells (25 days, unpublished data), which react to CPT-11 with a particularly strong and long-lasting cell cycle arrest (Magrini et al, 2002).…”

Counting Heads in the War against Cancer: Defining the Role of Annexin A5 Imaging in Cancer Treatment and Surveillance

“…After evaluating extensively the huge arsenal of available experimental and clinical data, Brown and Attardi recently concluded that at least for nonhematologic cancers, no such pattern could be distinguished (13). The discussed data comprise a spread of apoptotic deficiencies, including p53 knockouts (14,15) and models of overexpression of the proapoptotic protein Bcl-2 (16), as well as other members of the Bcl-2 family (17). Together, these findings strongly indicate that the apoptotic capabilities of cells have marginal influence on cell survival following DNA damage.…”

Irinotecan-Induced Apoptosis Is Inhibited by Increased P-Glycoprotein Expression and Decreased p53 in Human Hepatocellular Carcinoma Cells

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