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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...

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Purpose: The purpose of the present study was to evaluate the antitumor activity and pharmacokinetic profile of MEN4901/T-0128 in nude mice bearing human tumor xenografts in comparison with irinotecan (CPT-11) and T-2513. Experimental Design: We have determined the antitumor activity of MEN4901/T-0128, CPT-11, and T-2513 in BALB/cA Jcl nude mice bearing human gastric (H-81), colon (H-110), lung (Mqnu-1, H-74), esophageal (H-204), liver (H-181), and pancreatic (H-48) cancer lines, which had been serially transplanted s.c. and maintained in nude mice, and characterized the pharmacokinetic profile of MEN4901/T-0128 in nude mice bearing human gastric carcinoma St-4. Results: MEN4901/T-0128 administered i.v. showed a marked antitumor activity in each of these tumor models, producing tumor shrinkage in the models of H-204 and H-181 carcinomas at its maximum tolerated dose of 80 mg/kg (expressed as T-2513) weekly for 4 weeks (q7d × 4) and tumor-shrinking or marked growth-inhibitory effects in the models of H-81, H-110, Mqnu-1, H-74, and H-48 carcinomas at 1/3 of its maximum tolerated dose (q7d × 4). Pharmacokinetic analysis showed that MEN4901/T-0128 had an extended plasma half-life with sustained tumor levels of T-2513, which may explain the superior activity of MEN4901/T-0128 in vivo. Conclusions: Because the efficacies of some drugs in this human cancer-nude mouse panel correlated well with their clinical outcomes in patients with the same type of cancers, the findings provide direct support that MEN4901/T-0128 is more efficacious than CPT-11 and is an excellent candidate for clinical trials for the treatment of solid tumors.