Associations of various gene polymorphisms with toxicity in colorectal cancer patients receiving oral uracil and tegafur plus leucovorin: a prospective study.

BACKGROUND: To assess the predictive value of polymorphism in nine genes, primarily thymidylate synthase (TS) and orotate phosphoribosyltransferase (OPRT), which relates to 5-fluorouracil (5-FU) metabolism, for toxicity in patients treated with oral uracil/tegafur (UFT) plus leucovorin (LV). PATIENTS AND METHODS: We treated 99 patients with stage II or III colorectal carcinoma with oral UFT + LV. Germline DNA from patients was genotyped for 5-FU and folate metabolism-relating genes. CYP2A6, tegafur-activating enzyme, and uridine diphosphate-glucuronosyltransferase 1A1 genetic variation were also assessed. Toxicity was graded by the National Cancer Institute Common Toxicity Criteria, version 2.0. RESULTS: The multivariate logistic regression revealed that OPRT 638G>C polymorphism was associated with grade 3 diarrhea [odds ratio (OR) 19.84 for patients with the C/C homozygous type compared with patients with wild type, P = 0.014] and polymorphisms of UGT1A1 were associated with hyperbilirubinemia (OR 38.76 for homozygotes and double heterozygotes of *6 or *28 compared with wild type, P = 0.0008). No relationships were observed between TS polymorphisms and any toxicity. CONCLUSIONS: OPRT polymorphism predicts toxicity, especially grade 3 or greater diarrhea to oral UFT + LV adjuvant chemotherapy, whereas TS does not, in our study cohort. UGT1A1 polymorphism seems to be a risk factor for hyperbilirubinemia due to UFT+LV.

Randomized clinical trial of the influence of mechanical bowel preparation on faecal microflora in patients undergoing colonic cancer resection.

BACKGROUND: This study investigated the influence of mechanical bowel preparation (MBP) on faecal microflora, using rRNA-targeted reverse transcription-quantitative polymerase chain reaction in patients undergoing colonic cancer resection. METHODS: Forty-two patients undergoing elective colonic surgery were randomized into MBP or no-MBP groups (21 in each group). The main outcome was the bacterial microflora and faecal organic acid content of faecal material obtained at operation. RESULTS: Clinical characteristics were similar in the two groups. Bowel content in the resected specimens did not differ significantly. The count of bacterial microflora, such as Bifidobacterium and total Lactobacillus, in both intraoperative faecal material and first material after surgery was significantly lower in the MBP group than the no-MBP group (P < 0·050). Levels of faecal organic acids, such as acetic acid, propionic acid and butyric acid, in intraoperative faecal material were significantly lower, and levels of lactic acid were significantly higher, in the MBP group than in the no-MBP group (P < 0·050). The succinic acid level was significantly higher after surgery than before operation in the MBP group (P = 0·008). CONCLUSION: Preoperative MBP caused an imbalance in the bowel microflora, suggesting that it offers no advantages in terms of enterobacterial microflora for patients undergoing colonic cancer resection. REGISTRATION NUMBER: UMIN000003153 (http://www.umin.ac.jp/ctr/index.htm).

Antitumor effect of S-1 on DMH induced colon cancer in rats.

The aim of this study was to establish an autochthonous colon cancer model in the rat as an in vivo secondary screen for the general evaluation of new anticancer agents against colorectal cancer, and also to evaluate practically the antitumor activity of 1M tegafur-0.4M 5- chloro-2,4-dihydroxypyridine-1M potassium oxonate(S-1), a new p.o. fluoropyrimidine. Thirty-two Sprague-Dawley rats received dimethlhydrazine(40 mg/kg) s.c. once weekly for 10 weeks to induce colon cancer.20 weeks after beginning the carcinogen treatment, a barium enema was performed to visualize tumors. The animals were divided into a control group and S-1 treatment group. After 5 weeks of treatment, the barium enema was repeated. The mean doubling time of 24 tumors in the control group was 19.0 + 8.4 (SD) days. Response to S-1 was judged as effective when the doubling time exceeded 35.8 days, calculated from the mean + 2SDs in the control group. The response rate of S-1 was 55%, 34% of the tumors were decreased in size after treatment. This figure was higher than that of clinically-used 5-fluorouracil(5-FU) derivatives; 5-FU;6%, Tegafur(FT):6%, 1M tegafur-4M uracil(UFT):14%, reported in our previous study. An autochthonous colon cancer model is useful to evaluate the clinical therapeutic efficacy of drugs for colorectal cancer, and S-1 is expected to have a high therapeutic effect on human colorectal cancer.

[A model for sensitivity determination of anticancer agents against chemical-induced colon cancer in rats].

Chemically-induced colon cancer was used to test the sensitivity of tumors to chemotherapeutic agents. Thirty-four Sprague-Dawley rats received dimethylhydrazine (40 mg/kg) s.c. once weekly for 10 weeks to induce colon cancer. Twenty weeks after beginning the carcinogen treatment, a barium enema was performed to determine the size of colon tumors. The animals were divided into CDDP group and CPT-11 group, in which the maximum tolerable dose of each drug was given. After 5 weeks of treatment, the barium enema was repeated. "Response" was assessed on the basis of tumor doubling time. Response rates in the CDDP and CPT-11 groups were 6% and 35%, respectively. This reflects the clinical data of those drugs and confirms the results of our previous study. The present study may be a predictive model for screening anticancer drugs for human colorectal malignancy.

Growth rate of experimental colon cancer in the absence of fecal stream and antitumor effect of UFT in rats.

Growth rate of a chemically-induced colon tumor in the absence of fecal stream was investigated and the tumors to a chemotherapeutic agent tested. Eighty Sprague-Dawley rats received dimethylhydrazine (40 mg/kg) s.c. once weekly for 10 wk to induce colon cancer. Then a colostomy was performed to produce a defunctioning colon without fecal stream. 22 wk after beginning the carcinogen treatment, a barium enema was performed to visualize tumors in the defunctionalized colon. 29 rats died postoperatively and 16 had no tumor radiographically. The remaining 35 rats were divided into a control group and UFT treatment group. After 5 wk of treatment, the barium enema was repeated. The mean doubling time of 19 tumors in the control group was 9.8 days +/- 4.0 (SD). Response to UFT was judged as effective when the doubling time exceeded 17.8 days, calculated from the mean +/- 2SDs in the control group. The response rate of UFT was 48%. The growth rate of colon tumors without fecal stream was faster and more stable than those with fecal stream; as a result, the sensitivity to UFT became higher than that in tumors with fecal stream (36%), which was reported in our previous study. The present experimental system may be more accurate for assessing the response to chemotherapeutic agents.

[Cochlear microphonic potential (CM) recordable at non-shielded bedside--with reference to the development of a new earphone (NC-3)].

By making several improvements in current hearing aid earphones, a new earphone (NC-3) for CM measurement in electrocochleography (ECochG) has been developed. A silicone tube with a 1.5mm inside diameter, 175mm in length, was attached to the acoustic hole side of the earphone. The earphone proper was shielded with aluminum foil and one end of the foil was connected to a low noise cable. Human forearm was used as a dummy ear and the electrode HN-5 was fixed thereon, and a sound stimulus of 90dBnHL was delivered by the earphone (NC-3). No measurable artifacts, such as electromagnetic conductions and the CM-like mechanical vibrations generated by the acoustic output system, were recorded. By placing the earphone (NC-3) from a right-angle to a diagonal direction toward the electrode circuit, electromagnetic conduction contamination was prevented. With an extratympanic procedure using the electrode HN-5, ECochG-CM was recorded from normal hearing subjects in both a shielded sound-proof room and a non-shielded ordinary but quiet room. Short tone bursts at 1 and 4kHz were employed as acoustic stimuli and delivered by the earphone (NC-3). In the non-shielded quiet room, no electromagnetic conduction contamination or mechanical vibration was observed and there were no differences in CM responses between the two rooms. These results suggest that this earphone (NC-3), making CM recordings possible at the ordinary bedside without shielding, may contribute significantly to the subsequent spread of ECochG-CM measurement, by compensating for the disadvantages of a loudspeaker.

[Studies on respiratory infections in primary care clinic (V). The pattern of distribution on bacteria, Mycoplasma pneumoniae and virus isolated from patients with respiratory infections, who were seen in six private clinics, and clinical efficacy of ciprofloxacin and roxithromycin].

The pattern of distribution of bacteria, Mycoplasma pneumoniae and virus isolated from the same specimen recovered from the throat swab or the sputum of 479 patients with respiratory infections who were seen in six private clinics in Sendai City of Japan during the period from October to November in 1992 (period I) and from January to February in 1993 (period II) was documented. Of the 479 patients, 234 had acute pharyngitis, 145 had acute bronchitis, 96 had influenza, 21 had acute tonsillitis, 5 had acute pneumonia and 9 had other respiratory infections. One hundred (42.4%) strains of potential pathogen and one strain of M. pneumoniae were recovered from 236 cases in period I, and 66 (27.2%) strains of potential pathogen, one strain of M. pneumonae and 73 strains of Influenza virus (30.0%: 43 of type A Hong-Kong and 30 of type B) from 243 cases in period II. Of the 166 strains, major isolates were Staphylococcus aureus (56 strains), Streptococcus pneumoniae (12 strains), Streptococcus pyogenes (15 strains), Haemophilus influenzae (17 strains), Esherichia coli (4 strains), Klebsiella spp. (35 strains), Pseudomonas aeruginosa (4 strains) and Acinetobacter spp. (23 strains). Only one strain of S. aureus was resistant to methicillin (MIC: 50 micrograms/ml). None of S. pneumoniae was resistant to 1 microgram/ml of ampicillin. Ciprofloxacin was administered to 113 cases and roxythromycin to 220 cases by doctors in charge.(ABSTRACT TRUNCATED AT 250 WORDS)

A model for sensitivity determination of anticancer agents against chemically-induced colon cancer in rats.

Chemically-induced colon cancer was used to test the sensitivity of tumors to chemotherapeutic agents. Seventy-one Sprague-Dawley rats received dimethylhydrazine (20mg/kg) s.c. once weekly for 20 weeks to induce colon cancer. Then a barium enema was performed to see the size of colon tumors. The animals were divided into three groups that were subjected to the following treatments: 5-fluorouracil (5 FU); 1-(2-tetrahydrofuryl)-5 FU(FT); and a mixture of FT and uracil (UFT). After 5 weeks of treatment, the barium enema was repeated. "Response" was assessed on the basis of tumor doubling time. Response rates in the 5-FU, FT, and UFT groups were 25%, 33% and 36%, respectively and this reflects the clinical data of these drugs. The present system may be a predictive model for screening anticancer drugs for human colorectal cancer.

Reduced growth rate of dimethylhydrazine-induced colon tumors in rats.

alpha-Difluoromethylornithine (DFMO) treatment has been shown to modify carcinogenesis in many experimental tumor models, including breast, urinary bladder, and colon. This study was designed to determine whether DFMO treatment can inhibit tumor growth on chemical-induced colon cancer in rats. Effectiveness of DFMO in combination with mitomycin C (MMC) was also evaluated. Forty-two Sprague-Dawley rats received dimethylhydrazine (20 mg/kg) s.c. once weekly for 20 wk to induce colon cancer. Then a double-contrast barium enema was performed, and colon tumors were detected. The animals were divided into four groups that were subjected to the following treatment: none; DFMO alone; MMC alone; and a combination of DFMO plus MMC. After 5 wk of treatment, the barium enema was repeated. For the evaluation of treatment efficacy, tumor doubling time was adopted. The mean tumor doubling time in the control group was 20.7 +/- 9.1 days (SD). "Response" was judged as effective when tumor doubling time in treatment groups was more than 38.9 days, calculated from the mean + 2 SDs in the control group. Response rates in the DFMO, MMC, and DFMO plus MMC groups were 40.0%, 10.0%, and 82.3%, respectively. DFMO was a more effective inhibitor of tumor growth than MMC, and DFMO in combination with MMC resulted in a synergic diminution of tumor growth. The double-contrast barium enema is useful to observe sequential tumor growth and may be appropriate for the evaluation of new treatment on experimental colon cancer in rats.

[Growth rate of experimental colonic cancer in rats].

Colonic cancers were induced in rats by subcutaneous injection of 1,2-Dimethylhydrazine. Tumor growth patterns were estimated by means of a double contrast barium enema technique. Tumor growth was almost exponential and the average doubling time was 20 +/- 5 (m +/- S.D.) days, at which time three different types of tumor growth patterns: Constant type, decreasing type and reaccelerating type, were noted. Serial double contrast barium enema technique appeared to be an useful method of studying in vivo primary colonic cancer growth patterns in rats.