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...
A series of 8‐substituted‐7‐fluoro‐5‐oxo‐5H‐thiazolo[3,2‐a]quinoline‐4‐carboxylic acids was prepared and evaluated for antibacterial activity. These compounds were synthesized from ethyl 2‐mercaptoquinoline‐3‐carboxylates 17 which were obtained from anilines 11 by a route involving an intramolecular cyclization reaction.
NM441 is a lipophilic prodrug of a new thiazeto-quinoline carboxylic acid derivative NM394, and when it is administered orally it is readily absorbed and hydrolyzed to its parent compound. After oral administration of NM441 at a dose of 20 mg/kg to dogs, the peak concentration of NM394 in plasma was 2.39 ,&g/ml, whereas it was 0.63 ,ug/ml for NM394 administered alone. In the course of our search for a new 6-fluoroquinolone antibacterial agent, thiazeto-quinoline carboxylic acid derivatives with a sulfur atom at the C-2 position were tested, and a new compound, NM394, 6-fluoro-1-methyl-7-(1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid, was chosen as the most promising compound with potent antibacterial activity in vitro (7). However, despite its broad spectrum of activity, the protective effect ofNM394 against experimental infections is poor when it is administered orally. In order to increase the absorption of NM394 from the intestinal tract, the prodrug of NM394, NM441, 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo -1,3 -dioxolen -4 -yl)methyl-1 -piperazinyl] -4 -oxo-4H- [1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid, was synthesized ( Fig. 1). When NM441 was administered orally, it was readily absorbed and hydrolyzed to its parent compound, NM394, in blood and showed an excellent protective effect against experimental infections in mice. In this study, we compared the in vivo antibacterial activity and pharmacokinetic parameters of NM441 dosed orally compared with those of ciprofloxacin (11), ofloxacin (9) and enoxacin (4) and determined the pharmacokinetics of NM394 and NM441 in dogs.
A series of [1,3]thiazeto[3,2-a]quinoline-3-carboxylic acids and their esters were prepared and evaluated for antibacterial activity. The derivatives with a hydrogen or methyl group at C-1, fluorine at C-6, and piperazinyl or 4-methyl-1-piperazinyl group at C-7 showed superior in vitro antibacterial activity, and the derivatives with 4-methyl-1-piperazinyl group at C-7 had potent in vivo activity. Compound 29a (NM394) showed excellent in vitro antibacterial activity and low toxicity but poor absorption from the gastrointestinal tract. Compound 29ee (NM441), an N-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl] derivative of 29a, was found to possess a favorable pharmacokinetic profile and oral activity superior to that of ciprofloxacin in experimental animals.
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