Biomedical subjects

M Kitajima

Publications and source records attributed to M Kitajima.

At least 433 records · Page 24Linked to original sources

PubMedDate not supplied

Epidermal growth factor receptor-dependent cytotoxic effect of anti-EGFR antibody-ribonuclease conjugate on human cancer cells.

We have conjugated the murine monoclonal antibody (528) against the human epidermal growth factor receptor (EGFR) to mammalian pancreatic ribonuclease (RNase) via N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP) and 2-iminothiolene (2-IT). The conjugate showed dose-dependent cytotoxicity against EGFR-producing squamous cancer cells (A431, TE8, TE5, Ca9-22) and no detectable cytotoxicity against EGFR-deficient small-cell lung cancer cells (H69). The cytotoxicity of the conjugate was positively correlated with the EGFR numbers of each cell line. The addition of excess 528 antibody to the medium protected A431 cells from the conjugate cytotoxicity. This immunoconjugate might be useful for targeted treatment of squamous cell carcinomas hyperexpressing EGFR.

Animals↗

PubMedDate not supplied

Serum tartrate resistant acid phosphatase as a potential marker of bone metastasis from breast cancer.

BACKGROUND: Tartrate resistant acid phosphatase (TRACP) is exclusively localized in osteoclasts and has been suggested to be a unique marker of bone metastasis. PATIENTS AND METHODS: TRACP activity using an improved spectrophotometric assay was measured in 56 healthy volunteers and 113 breast cancer patients, including 35 with bone metastases (BM). RESULTS: TRACP activities (IU/l, mean +/- SD) of normal subjects in pre- and post-menopausal women were 5.7 +/- 1.3 and 6.6 +/- 1.2, respectively (p < 0.02). The specificity, sensitivity, and accuracy of TRACP in patients, were 91.0%, 65.7%, and 83.2%, respectively. TRACP was significantly higher in patients with BM than in patients without BM (p < 0.01). In patients with BM, TRACP increased in proportion to the number of BM. Regarding clinical assessment of treatment of BM, TRACP was significantly higher in patients with progressive disease. CONCLUSION: TRACP is a useful marker of metastatic bone disease and response to treatment in breast cancer patients.

Acid Phosphatase↗

PubMedDate not supplied

Chemosensitivity test is useful in evaluating the appropriate adjuvant cancer chemotherapy for stage III non-scirrhous and scirrhous gastric cancers.

A total of 183 cases with gastric cancer was retrospectively analyzed in terms of their chemosensitivity as determined by the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay and their survival rates after surgery. After the patients were stratified into scirrhous or non-scirrhous carcinoma groups, they were tested for stage III or IV gastric cancer. In these four cohorts, the patients were categorized into sensitive and insensitive groups determined by the MTT assay. The sensitive group was treated with at least one drug that had been shown to be effective in the MTT assay, and the insensitive group was given a drug that had been shown to be ineffective in the MTT assay. In stage III gastric cancer, the sensitive group showed a favorable survival compared to the insensitive group in scirrhous and non-scirrhous carcinoma, while this difference was diminished in stage IV gastric cancer. There were no survival benefits in the sensitive group in stage III gastric cancer, when they were not treated with adjuvant cancer chemotherapy. These results suggested that MTT assay would be useful in evaluating the appropriate adjuvant cancer chemotherapy for stage III scirrhous and non-scirrhous gastric cancer.

Adenocarcinoma, Scirrhous↗

PubMedDate not supplied

Chemosensitivity testing of primary tumor cells from gastric cancer patients with liver metastasis can identify effective antitumor drugs.

The liver metastasis of gastric carcinoma is resistant to conventionally available treatment. Twenty patients with liver metastasis of gastric cancer were treated by arterial drug infusion using a reservoir and seven cases were treated with systemic chemotherapy. The resected primary gastric cancer specimen was used for chemosensitivity assay with 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) endpoint, and the patients were treated without reference to the results of the chemosensitivity assay. The mean survival period was assessed according to the histology of the primary lesion, the grade of liver metastasis and, the presence of peritoneal dissemination. No significant differences were observed in the primary tumor histology and grade of liver metastasis, but the survival period of the patients with liver metastasis and peritoneal dissemination was significantly shorter than that of the patients without peritoneal dissemination. Nine patients were treated with drugs that were effective in the chemosensitivity assay, and their responses included two complete responses and two partial responses; these patients showed a significantly prolonged survival period compared with patients treated with drugs that were not effective in the assay. The chemosensitivity assay is useful for evaluating the effectiveness of antitumor agents against liver metastasis of gastric cancer.

Adult↗

PubMedDate not supplied

Thymidylate synthetase and dihydropyrimidine dehydrogenase levels in gastric cancer.

The measurement of thymidylate synthetase (TS) and dihydropyrimidine dehydrogenase (DPD) enzymatic activities and mRNA levels in tumors may be useful in predicting tumor sensitivity to 5-fluorouracil (5-FU). Forty-one patients with advanced gastric cancer gave informed consent and were enrolled in this study. Biopsy specimens of gastric cancer were obtained preoperatively through gastrofiberscopy and used to determine TS and DPD mRNA levels. We also measured TS and DPD enzymatic activities and mRNA levels in surgically resected gastric cancer samples, as well as in adjacent normal gastric mucosa. TS and DPD activities were measured using the TS-binding assay and a radioenzymatic assay, respectively, while mRNA levels were measured by semi-quantitative reverse transcription-PCR (RT-PCR) co-amplified with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as an internal standard. In resected tumor specimens, TS and DPD activities ranged from 7.1 to 176.6 fmol/mg protein and from 3.6 to 99.8 pmol/min/mg protein, respectively, while TS and DPD mRNA levels ranged from 0.50 to 21.12 and from 0.014 to 7:22, respectively. There were no significant correlations between TS/DPD levels and other clinicopathological factors, except for low DPD mRNA levels in undifferentiated carcinoma. Both TS activity and mRNA levels were significantly higher in tumor tissues compared to normal adjacent mucosa. In contrast, there was no significant difference between tumoral and non-tumoral DPD activity, although tumor tissue showed significantly lower DPD mRNA levels than non-tumoral tissue. High tumoral TS mRNA levels in preoperative biopsy specimens from patients with stage III/IV was associated with poor survival outcome after surgery compared with patients with low tumoral TS mRNA levels. In contrast, DPD levels had no influence on prognosis. We conclude that high tumoral TS levels and low tumoral DPD mRNA may indicate the selective cytotoxicity of 5-FU on gastric cancer, and that tumoral TS mRNA levels may be a prognostic factor for patients with stage III/IV gastric cancer.

Aged↗

PubMedDate not supplied

Combined resection of the portal vein for pancreatic cancer: preoperative diagnosis of invasion by portography and prognosis.

BACKGROUND/AIMS: Pancreatic cancer often invades the portal vein because of the anatomical position. Pancreatic cancer with portal vein invasion was not considered operable, and thus the resectability rate was low. METHODOLOGY: Between March 1976 and February 1994, 140 of 243 patients underwent resection, a resectability rate of 58%. A total of 81 (58%) of these patients underwent portal vein resection. We assessed 56 patients in whom the depth of invasion had already been determined histopathologically and whose superior mesenteric arterial portograms were readable. The 56 patients were classified into 4 groups: normal (Type I), stricture on one side of the portal vein (Type II), stricture on both sides of the portal vein (Type III), complete obstruction (Type IV). The length of the longitudinal lesions on portograms was also measured. RESULTS: In 93% (27/29 cases) of portographic Type I or II lesions with longitudinal lesions of 2 cm or less, portal vein invasion was limited to the tunica media. No patients with cancer invasion into the lumen survived more than 1 year. CONCLUSIONS: For patients with pancreatic cancer Type I or II, preoperative portography findings and longitudinal lesions of 2 cm or less, portal vein resection is indicated, and long-term survival can be expected.

Adult↗

PubMedDate not supplied

Cumulative results of chemosensitivity tests for antitumor agents in Japan. Japan Research Society for Appropriate Cancer Chemotherapy.

The Japan Research Society for Appropriate Cancer Chemotherapy set out to summarize the present status of chemosensitivity testing for antitumor agents in Japan. Two different questionnaires were sent to 122 and 94 institutes, respectively, whilst responses were received from 87 (71.3%) and 41 (43%) institutes, respectively. The results showed that chemosensitivity tests were performed in 42 institutes where a total of 2 in vivo and 10 in vitro different assays were performed. Actual cases of chemosensitivity detected by the tests varied from 1 to 368 cases/year/institute with a median of 15 cases and mean +/- standard deviation of 48 +/- 65 cases. The total number of tested cases increased from 1,747 cases in 1993 to 1,934 cases in 1994 and to 2,147 cases in 1995, resulting in an average of 1,891 cases year. The assays used included the adenosine triphopsphate inhibition assay,/the collagen droplet embed drug response assay, the fluorescent dye assay, the growth chamber assay, the histoculture drug response assay, human tumor clonogenic assay, the MTT assay (SDI test), the nuclear damage assay, the nude mouse model, the subrenal capsule assay and the thymidine incorporation assay (scintillation assay). The correlation of in vitro and in vivo results revealed 215 true positive (S/S), 246 false positive (S/R), 45 false negative (R/S) and 595 true negative (R/R) cases, resulting in rates of 47% for true positives and 93% for true negatives, with a 74% accuracy. We concluded that chemosensitivity testing is widely applied in this country and has a high accurate predictive value for advanced carcinomas.

Animals↗

PubMedDate not supplied

Oncologic outcome of laparoscopic versus open surgery for advanced colorectal cancer.

BACKGROUND/AIMS: Laparoscopic colorectal surgery for advanced colorectal carcinoma still remains controversial because of the technical difficulties in lymph node dissection, which is a routine procedure for advanced colorectal carcinoma, and uncertainty regarding the oncologic outcome after laparoscopic colectomy. This study reviewed the results of laparoscopic colectomy with lymph node dissection in patients with advanced colorectal carcinoma performed at our hospital. METHODOLOGY: The oncologic outcomes of 48 patients with advanced colorectal carcinoma who underwent laparoscopic colectomy between 1993 and 1998 were compared with those of 48 matched patients who underwent conventional open surgery during the same period or immediately before the introduction of laparoscopic surgery. RESULTS: The median follow-up for the laparoscopic group and the open colectomy group was 41 and 68 months, respectively. No port site recurrence occurred in the laparoscopic group, and the medium-term disease-free rate, overall survival rate, as well as the patterns of recurrence were comparable in the two groups. CONCLUSIONS: Oncologic outcome of laparoscopic colectomy at a minimum of two years was not compromised compared with conventional open surgery even in advanced carcinoma. However, information regarding true oncologic outcome will require careful long-term follow-up.

Aged↗

PubMedDate not supplied

Docetaxel enhances the cytotoxicity of tetrahydropyranyladriamycin in a sequence-dependent manner.

BACKGROUND: Taxanes and anthracyclines are active against breast cancer. In this study we investigated the combined antitumor activity of these drugs, with particular regard to sequence-dependency. MATERIALS AND METHODS: The combined antitumor activity of docetaxel and tetrahydropyranyladriamycin (THP) against two human breast cancer xenografts was assessed using an in vitro histoculture drug-response assay. The sequence-dependency of the combined cytotoxicity was evaluated by isobologram. RESULTS: A synergistic antitumor activity of combined docetaxel + THP was exhibited against the R-27 xenograft when docetaxel was given first or simultaneously with THP. However, this synergism was diminished when THP was used before docetaxel. While an additive effect of combined docetaxel + THP was observed against MX-1 xenograft when docetaxel was given first or simultaneously with THP, this effect was not marked using the THP/docetaxel sequence. CONCLUSION: Docetaxel increased the antitumor activity of THP, but only when administered before or simultaneously with THP.

Adult↗

PubMedDate not supplied

Chemosensitivity testing of clinical gastrointestinal cancers using histoculture and the MTT end-point.

Three-dimensional histoculture with the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) end-point was utilized for chemosensitivity testing of 100 clinical gastrointestinal cancers and the results were compared with those obtained with cell-suspension culture with the MTT end-point. Of the 100 surgical specimens, 91 were evaluable using histoculture assay and 66 were evaluable using the cell-suspension assay. When the assay results were compared with historical frequency of clinical response to chemotherapy, the results of the histoculture assay showed a closer correlation than those of the cell-suspension assay. Therefore, the histoculture assay seems to have a higher evaluability rate and a closer correlation with clinical chemosensitivity of gastrointestinal cancers than the cell-suspension assay.

Antineoplastic Agents↗

PubMedDate not supplied

Modulation by l-leucovorin of 1-hexylcarbamoyl-5-fluorouracil antitumor activity on human gastric and colon carcinomas serially transplanted into nude mice.

Experimental biochemical modulation of 1-hexylcarbamoyl-5-fluorouracil (HCFU) with l-leucovorin (LV) was carried out using human gastric (H-111) and colon (Co-4) carcinoma xenografts serially transplanted into nude mice. Thirty-five or 70 mg/kg HCFU dissolved in 0.2 ml of 1% hydroxymethyl cellulose was administered po daily for 3 weeks except Sundays, and 50, 100, 200 or 300 mg/kg LV dissolved in 0.2 ml physiological saline was administered po 30 min before administration of HCFU. The biochemically modulated antitumor activity was evaluated in terms of actual tumor weight, the relative mean tumor weight and the degree of inhibition of thymidylate synthetase (TS) in the tumors at the end of the experiments, assayed according to the method of Spears et al. Although 35 mg/kg HCFU was ineffective against gastric carcinoma H-111, combination with 200 or 300 mg/kg LV resulted in a positive antitumor effect of HCFU on this strain without any increase of side effects in terms of body weight loss and mouse mortality. The colon carcinoma strain Co-4 showed marginal sensitivity to HCFU (35 mg/kg) alone, but 50 or 100 mg/kg LV modulated the antitumor activity of HCFU on Co-4 to produce a significant positive effect without any increase in toxicity, and HCFU administered with 100 mg/kg LV was more effective than the maximum tolerated dose of HCFU (70 mg/kg) alone. The TS inhibition rate was closely related to the biochemical modulation of HCFU antitumor activity by LV, suggesting that the modulation involves an increase of the ternary complex of TS, 5,10-methylene tetrahydrofolate from LV and 5-fluorodeoxyuridine 5'-monophosphate (FdUMP). Combination of HCFU and LV is therefore thought to be useful in increasing the antitumor activity of HCFU on gastrointestinal carcinomas without enhancing its toxicity.

Animals↗

PubMedDate not supplied

Human tumors are methionine dependent in vivo.

Methionine-dependence is a tumor-specific biochemical defect expressed by the inability or decreased ability of tumors to grow under the condition of methionine-depletion. Many reports have shown that methionine-dependence occurs in human tumors of all types, including fresh surgical specimens in vitro. However, in vivo determinations of methionine-dependence have thus far been made only in rodent malignant tumors using methionine-deficient diets. We report here for the first time that human cancer xenografts in nude mice are methionine-dependent and when fed a methionine-free diet tumor growth is greatly inhibited. The body weight of mice on the methionine-free diet was found to be maintainable by once-per-week administration of methionine. The data presented here suggest that methionine-dependence can be an important target for human cancer treatment.

Animals↗

PubMedDate not supplied

Growth regulation by estradiol, progesterone and recombinant human epidermal growth factor of human breast carcinoma xenografts grown serially in nude mice.

Four human breast carcinoma xenografts, MCF-7, Br-10, T-61 and MX-1, were transplanted into female nude mice with or without pretreatment with estradiol and progesterone. Hormone receptors including cytosol and nuclear estrogen receptor (ERc and ERn) and progesterone receptor (PgR) were assessed by the dextran-coated charcoal method and exchange assay; epidermal growth factor receptor (EGFR) was measured by the 125I-EGF binding assay. MCF-7 and T-61 were ERc-, ERn- and PgR- positive, but Br-10 was positive only for ERc; MX-1 was negative for these hormone receptors, but was the only xenograft showing EGFR. The growth of MCF-7 and Br-10 was enhanced by exogenous estradiol and progesterone, whereas the growth of T-61 was markedly inhibited by exogenous estradiol; the growth of MX-1 was not influenced by these sex steroids. Recombinant human epidermal growth factor (rhEGF) inhibited the growth of EGFR-positive MX-1 dose-dependently, whereas no changes were observed in the growth of EGFR-negative MCF-7, Br-10 and T-61 after treatment with rhEGF. This paradoxical inhibition of rhEGF on EGFR-positive MX-1 might be due to down-regulation of EGFR, as shown in the ER-positive xenograft T-61, whose growth was inhibited by estradiol.

Animals↗

PubMedDate not supplied

Recombinant human interferon alpha-2a increases the antitumor activity of 5-fluorouracil on human colon carcinoma xenograft Co-4 without any change in 5-FU pharmacokinetics.

We investigated the modulating effect of recombinant human interferon alpha-2a (IFN-alpha) on the antitumor activity of 5-fluorouracil (5-FU) against a human colon carcinoma xenograft (Co-4) in nude mice with reference to changes in the pharmacokinetic pattern of 5-FU. Mice bearing Co-4 received 5-FU ip at a dose of 90 mg/kg once with or without IFN-alpha, which was administered sc at a dose of 60.000 IU/mouse daily for 7 days before 5-FU treatment. When the area under the curve (AUC) and peak plasma concentration (Cmax) of 5-FU with or without IFN-alpha were measured as pharmacokinetic parameters, the pharmacokinetics of 5-FU was not changed by IFN-alpha administration. This result suggests that the modulating effect of IFN-alpha on 5-FU does not involve augmentation of 5-FU pharmacokinetic parameters.

Animals↗

PubMedDate not supplied

Antitumor activity of hexamethylmelamine on human tumor xenografts serially transplanted in nude mice.

The antitumor activity of hexamethylmelamine (HMM) was evaluated using four human tumor xenografts serially transplanted in nude mice. HMM was dissolved in 0.2 ml of 1% hydroxypropyl cellulose per mouse and administered perorally daily, except on Sunday, for 4 weeks, giving an estimated maximum tolerated dose (MTD) of HMM of 75 mg/kg. The MX-1 cell line showed dose-dependent sensitivity to HMM and was completely eradicated by treatment at the MTD. The minimum effective dose of HMM against MX-1 was calculated to be 22.1 mg HMM/kg, resulting in the chemotherapeutic index of 3.4. The demethylated derivatives of HMM, pentamethylmelamine and tetramethylmelamine, were also effective against MX-1, whereas trimethylmelamine was ineffective. The effect of HMM was more marked when the drug was administered on day 1 after tumor inoculation, compared with administration during the exponential growth phase. HMM is thought to be a promising agent for the treatment of several types of human carcinoma, producing active metabolites in vivo after peroral administration.

Altretamine↗

PubMedDate not supplied

Combined effect of 5-fluorouracil and carboplatin against human gastric cancer cell lines in vitro and in vivo.

The antitumor activity of a sequential combination of 5-fluorouracil (5-FU) and carboplatin (JM-8) was evaluated using gastric cancer cell lines in vitro and in vivo. In the in vitro study, the sequence of 5-FU followed by JM-8 showed higher antitumor activity than that of the reverse sequence. The sequence of 5-FU at 5 micrograms/ml for 24 h followed by 5 micrograms/ml JM-8 for 24 h showed antitumor activity almost equivalent to that of 10 micrograms/ml 5-FU for 24 h and higher activity than that of 10 micrograms/ml JM-8 for 24 h on two cell lines. To evaluate the antitumor activity and toxicity of 5-FU and JM-8 in vivo, BALB/cA nu/nu mice bearing human gastric cancer xenografts St-15, St-40 and SC-1-NU were administered 5-FU and JM-8 intraperitoneally. The sequence of 5-FU prior to JM-8 showed higher antitumor activity than that of the reverse sequence on all the xenografts, and simultaneous administration of 5-FU and JM-8 showed the most potent antitumor activity on St-40 and SC-1-NU. On the other hand, the sequence of 5-FU before JM-8 showed the lowest toxicity in all the treated groups, in terms of death rate, body weight loss and spleen weight loss. This combination is thought to be a promising chemotherapy regimen, showing high antitumor activity without an increment of toxicity.

Adenocarcinoma↗

PubMedDate not supplied

Antitumor activity of (2''R)-4'-O-tetrahydropyranyl adriamycin on human gastric cancer cell lines in vitro and in vivo.

The antitumor activity of (2''R)-4'-O-tetrahydropyranyl adriamycin (pirarubicin; THP) was assessed using human gastric cancer cell lines in vitro and in vivo. The cytotoxicity of THP on MKN-28 and MKN-45 was superior to that of adriamycin (ADM) as detected by a growth assay with an MTT colorimetric endpoint. When the same doses of THP and ADM were administered intraperitoneally to nude mice bearing St-15, St-40 and SC-1-NU, the antitumor activity of THP was almost equivalent to ADM in terms of relative mean tumor weight. However, the adverse effects of THP were also significantly lower than those of ADM in terms of death rate, body weight loss and spleen weight loss. This was also confirmed in THP or ADM combination chemotherapy with mitomycin C and 5-fluorouracil on St-15 and MKN-45. These results indicated that THP is a candidate anthracycline to replace ADM for combination cancer chemotherapy in gastric carcinoma.

Animals↗

PubMedDate not supplied

Recombinant human interferon alpha-2a increases 5-fluorouracil efficacy by elevating fluorouridine concentration in tumor tissue.

The modulating effect of recombinant human interferon alpha (IFN-alpha) on the antitumor efficacy of 5-fluorouracil (5-FU) against human carcinoma cell lines was investigated in vitro and in vivo. 5-FU, fluorouridine (FUR) or fluoro-5'-deoxyuridine (FUdR) were tested against cultured human colon tumor C-1 cells with or without IFN-alpha. The in vitro antitumor activity of 5-FU was enhanced by the addition of IFN-alpha, but IFN-alpha did not increase the effect of FUR or FUdR. The in vivo antitumor activity of 5-FU with or without IFN-alpha was assessed using Co-4, a human colon carcinoma xenograft, in nude mice. Thymidylate synthetase inhibition and concentration of FUR in the treated tumor tissues were concomitantly measured. A synergistic effect of 5-FU and IFN-alpha was observed on Co-4 in nude mice, and this in vivo synergism was obtained without any increment of thymidylate synthetase inhibition or side effects in terms of death rate and body weight loss. The intratumoral concentration of FUR was significantly increased by the addition of IFN-alpha in Co-4 tumor tissue treated with 5-FU. These results suggest that the mechanism of the combined effect of 5-FU and IFN-alpha is not related to enhancement of thymidylate synthetase inhibition, but to an increase of FUR concentration in the target tumor tissue. It is expected that this combination method will be clinically useful for the treatment of advanced colorectal carcinoma.

Animals↗