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T Kusumoto

Publications and source records attributed to T Kusumoto.

At least 73 records · Page 4Linked to original sources
PubMed1989

Hypoxia enhances the lethality of mitomycin C and carboquone against human malignant tumor cells in vitro.

Solid tumors contain hypoxic cells which are relatively resistant to antineoplastic activity of radiation or to chemotherapeutic agents. We determined the increase in antineoplastic activities of mitomycin C (MMC) and carboquone (CQ) against human tumor cells under conditions of in vitro hypoxia, with the following results. (a) The HeLa cells had been exposed to various concentrations of MMC or CQ for 2 h under normally aerated (about 20%) or hypoxic conditions (5.0 and 0%) and were maintained under normally aerated conditions for 3 days. The succinate dehydrogenase activity was assayed, using the succinate dehydrogenase inhibition (SDI) test. Treatment with MMC or CQ reduced the SD activity, compared to findings in the control cells, under hypoxic conditions. (b) The cells were exposed to the drug, MMC or CQ, under normally aerated or anoxic conditions, for 15-45 min and the colonies counted on day 14. Treatment with 0.45 microM of MMC for 45 min inhibited the clonogenicity of HeLa cells by 25.4% of findings in the control cells under anoxia. Treatment with 0.03 microM of CQ for 30 min inhibited the clonogenicity by 41.5%. (c) The sensitivity of 14 human tumor tissues (6 gastric and 8 colorectal cancers) to MMC or CQ under hypoxic conditions was determined, using the SDI test. MMC and CQ showed hypoxic enhancement. Therefore, MMC and CQ have definite positive effects on hypoxic cells, and hence a higher therapeutic ratio for treating clinical solid tumors.

Azirines↗
PubMed1989

In vitro sensitivity of various human tumors to 1-beta-D-arabinofuranosylcytosine and N4-behenoyl-1-beta-D-arabinofuranosylcytosine.

The sensitivities to 1-beta-D-arabinofuranosylcytosine (ara-C) and N4-behenoyl-1-beta-D-arabinofuranosylcytosine (BH-AC), a masked compound of ara-C, were determined in 33 human tumor tissues (11 gastric, 6 colorectal cancers and 16 malignant lymphomas), using the in vitro succinate dehydrogenase inhibition test. The succinate dehydrogenase (SD) activity of the tumor tissues was assayed following exposure to the drug at 8.8 or 88 microM for 3 days and the sensitivity was considered positive when the SD activity decreased to below 50% of that of the control cells at 88 microM. The SD activity decreased little at 8.8 microM and decreased individually at 88 microM. The mean of the SD activity at 88 microM was 65.7 +/- 11.5% for ara-C and 61.4 +/- 14.5% for BH-AC in gastrointestinal cancers, and 63.8 +/- 16.0% for ara-C and 58.3 +/- 18.3% for BH-AC in malignant lymphomas with a statistically significant difference (p less than 0.05). BH-AC is converted to ara-C for exertion of the cytotoxic effect and a positive correlation was noted between the SD activities of ara-C and BH-AC (r = 0.825 at 88 microM). The chemosensitivity varied with the tissue and 18% of the tissues were sensitive to ara-C, 27% to BH-AC and 15% were sensitive to BH-AC but resistant to ara-C. Our findings show that ara-C and BH-AC are equally cytostatic to human tumors. The sensitivity test of ara-C and BH-AC enables one to determine which drug is best suited for individual patients.

Antineoplastic Agents↗
PubMed1989

[Detection of cellular DNA strand breaks induced by antitumor drug and heat using in situ nick translation].

Cellular DNA strand break induced by an alkylating agent: Carboquone (CQ), and heat (43 degrees C) was detected in HeLa cells in vitro and mouse sarcoma-180 cells in vivo. The break sites in the DNA were translated artificially in the presence of Escherichia coli DNA polymerase I and [3H]-labeled dTTP and sites in the DNA were visualized by autoradiographic observation of grains in the nuclei. These breaks increased in a dose and time dependent manner, compared to findings in the control cells. Our findings show that the surviving response of cells decreases while the level of DNA strand breaks increases following exposure to CQ or heat. The nick translation method is a rapid in situ assay for determining drug and heat induced DNA damage of tumor cells, under in vitro and in vivo conditions and in a semi-quantitative manner.

Azirines↗
PubMed1989

Nick translation detection in situ of cellular DNA strand break induced by radiation.

DNA strand break in HeLa cells induced by radiation was detected using the in situ nick translation method. The cells were exposed to radiation of 3, 6, 12, 18, and 24 Gy in Lab-Tek tissue culture chamber/slides and were fixed with ethanol/acetic acid on the slide glass. The break sites in DNA were translated artificially in the presence of Escherichia coli DNA polymerase I and [3H]-labeled dTTP. Autoradiographic observation was made of the level of break sites in the DNA. The DNA strand break appeared even with a 3 Gy exposure, increased 8.6 times at 24 Gy compared with the control cells, and this level correlated reciprocally to change in cell viability. This nick translation method provides a rapid in situ assay for determining radiation-induced DNA damage of cultured cells, in a semi-quantitative manner.

Animals↗
PubMed1988

Potentiation of adriamycin cytotoxicity by dipyridamole against HeLa cells in vitro and sarcoma 180 cells in vivo.

Dipyridamole (DP) is clinically prescribed for its vasodilating and antiplatelet effects. DP also inhibits nucleoside transport and enhances cytostatic activity of antimetabolites. We obtained evidence for augmentation of the cytocidal effect of Adriamycin (ADM) by DP, both in vitro and in vivo. Nontoxic levels of DP enhanced the cytotoxicity of ADM against HeLa cells, and the 50% effective concentration of ADM was decreased 2.4-fold by DP. DP also increased the activity of ADM in clonogenic assays. Intracellular levels of ADM in the case of concomitant exposure to ADM and DP were 1.5-fold higher than in the case of exposure to ADM alone, determined using high-performance liquid chromatography. Incorporation of ADM into the cells pretreated with DP was also increased (1.4-fold), while the efflux was little affected. The growth of Sarcoma 180 tumors was prominently suppressed by the combination of ADM and DP, compared to findings with ADM alone. DP also prolonged the survival of Sarcoma 180 tumor-bearing mice, when given in combination with ADM. While the enhancement of cytostatic activity of antimetabolites has been attributed to a decrease in utilization of the salvage pathway by DP, our data show that the synergic effects of DP with ADM were the result of increased intracellular levels of ADM.

Animals↗
PubMed1988

Colorectal carcinoma in vitro is more sensitive to 1-hexylcarbamoyl-5-fluorouracil compared with six other antitumor drugs: carboquone, Adriamycin, mitomycin C, aclacinomycin A, cisplatin, 5-fluorouracil.

The sensitivity to 1-hexylcarbamoyl-5-fluorouracil (HCFU) of 25 colorectal cancer tissues was compared with that of six antitumor drugs: carboquone (CQ), Adriamycin (ADM), mitomycin C (MMC), aclacinomycin A (ACR), cisplatin (DDP), and 5-fluorouracil (5-FU), using the in vitro succinate dehydrogenase inhibition (SDI) test. Chemosensitivity was determined to be positive when the succinate dehydrogenase (SD) activity of the drug-exposed cells, at ten times the peak plasma concentration, was decreased to below 50 percent of that of control cells on day 3 of exposure. Decrease in SD activity was remarkable in cases of exposure to HCFU, compared with six other drugs. The sensitivity rates were 32 percent for CQ, 40 percent for ADM, 24 percent for MMC, 28 percent for ACR, 32 percent for DDP, 16 percent for 5-FU, and 68 percent for HCFU. The sensitivity rate for at least one of the six drugs (CQ, ADM, MMC, ACR, DDP, and 5-FU) was 52 percent, but was 80 percent when HCFU was taken into account. Since colorectal cancer tissues are resistant to various antitumor drugs, the chemosensitivity test of HCFU should aid in determining the effects of a particular drug for an individual patient.

Aclarubicin↗
PubMed1988

Sensitivity to six antitumor drugs differs between primary and metastatic liver cancers.

Chemosensitivity to six different types of antitumor drugs was assayed using the succinate dehydrogenase inhibition (SDI) test, with regard to effects of 29 tissues from primary hepatocellular carcinomas (PHC) and 12 metastatic liver cancers. Succinate dehydrogenase activity in the PHC was significantly decreased by adriamycin (ADM), mitomycin C (MMC), aclacinomycin A (ACR) (P less than 0.01), and 5-fluorouracil (5-FU), cisplatin (DDP) and carboquone (CQ) (P less than 0.05), as compared to findings in tissues from the metastatic liver tumors. In PHC, chemosensitivity to antitumor drugs in the SDI test was positive in 58.6% of tissues exposed to ADM, 60.7% with MMC, 11.1% with 5-FU, 65.4% with DDP, 65.5% with ACR and 64.3% with CQ. On the contrary, the positive rates seen in metastatic liver tissues were 18.2% in DDP and 8.3% in CQ, and there was no positive chemosensitivity in tissues exposed to ADM, MMC, 5-FU and ACR. Therefore, PHC will show a better response than metastatic liver cancers to antitumor drugs. Our observations show that the selection of sensitive drugs is most important to improve the response rate and the survival time of patients. The SDI test proves useful for planning clinical management.

Aclarubicin↗
PubMed1988

Excised human neoplastic tissues are more sensitive to heat than the adjacent normal tissues.

In tissues from patients subjected to gastrectomy or colectomy, the heat sensitivity was determined in the case of 23 neoplastic, 15 gastric, 8 colorectal, and the adjacent normal tissues, using the in vitro succinate dehydrogenase inhibition test. The succinate dehydrogenase (SD) activity of tissue fragments was assayed, following exposure to heat at 43 degrees C (heat treatment) or 37 degrees C (control) for 5, 10, 15 or 20 h. The sensitivity to heat treatment was estimated by the percentage of SD activity of the heat-treated cells, compared to that of control cells. The decrease in SD activity varied in the tumor tissue, following exposure to heat. The SD activity decreased to a greater extent in the tumor tissue than in the adjacent normal tissue, in each case. The mean +/- standard deviation of SD activity, following exposure to heat treatment for 20 h, was 32.1 +/- 14.0% for the tumour tissues and 52.4 +/- 10.4% for the adjacent normal tissues, with a statistically significant difference (p less than 0.01). These results show that the assay of heat sensitivity is meaningful for prediciting the effectiveness of hyperthermia and that hyperthermia has a selectivity for treating a malignant lesion.

Adult↗
PubMed1988

Sensitivity test for 5-fluorouracil and its analogues, 1-(2-tetrahydrofuryl)-5-fluorouracil, uracil/1-(2-tetrahydrofuryl)-5-fluorouracil (4:1) and 1-hexylcarbamoyl-5-fluorouracil, using the subrenal capsule assay.

The chemosensitivity of 20 human neoplastic tissues including 13 gastric and 7 colorectal cancers was tested using 5-fluorouracil (5-FU) and its analogues: 1-(2-tetrahydrofuryl)-5-FU (FT), uracil/FT (UFT) and 1-hexylcarbamoyl-5-FU (HCFU), and the in vivo subrenal capsule (SRC) assay. The relative variation of tumor size (delta TS/TSo) was calculated as follows: delta TS/TS0 = (TS6-TS0/TS0) x 100%, where TS6 was the tumor size on day 6 and TS0 on day 0, and the chemosensitivity was considered to be sensitive when delta TS/TS0 in the treated group was decreased to below -10%. The mean tumor size was -10.9 +/- (SD) 10.9% for 5-FU, -12.3 +/- 17.1% for FT, -18.4 +/- 15.8% for UFT and -17.9 +/- 15.4% for HCFU. The decrease of tumor size was marked when exposed to UFT (p less than 0.01) or HCFU (p less than 0.02), compared with that to 5-FU. Positive correlations were noted between the tumor sizes of 5-FU and its analogues (5-FU vs. FT, r = 0.851; 5-FU vs. UFT, r = 0.746; 5-FU vs. HCFU, r = 0.685). In 9 tissues resistant to 5-FU, 2 (22%) were sensitive to FT, 4 (44%) to UFT, 5 (56%) to HCFU and 7 tissues (78%) to at least one of these analogues. These results suggest that the SRC assay is useful for predicting the effective drug among 5-FU and 5-FU analogues, for individual patients with cancer.

Animals↗
PubMed1988

New cytoskeletal proteins are induced in HeLa cells by Vinca alkaloids.

The effects of Vinca alkaloids, vinblastine, vincristine, and vindesine, on protein synthesis were determined using HeLa cells. Vinblastine at the concentration of 1 microgram/ml induced new proteins, isoelectric points 4.8 and 7.0-7.5 and molecular weights 48 and 92 kd, in the HeLa cells, identified using two-dimensional gel electrophoresis. The 48-kd and the clustered (4-components) 92-kd proteins were also noted in HeLa cells treated with vincristine or vindesine. As most of the 48- and 92-kd proteins were Triton insoluble, they can be considered components of the cytoskeletal structure. Syntheses of these proteins were blocked by actinomycin D, therefore, new messenger RNA synthesis is required for induction. These proteins were not induced by an alkylating agent, antitumor antibiotics, or an antimetabolite. Our findings show that the 48- and the clustered 92-kd proteins are Vinca alkaloid reactive components and can be considered candidates for the elucidation of the antineoplastic effect of Vinca alkaloids.

Carbazilquinone↗
PubMed1988

Sodium succinate enhances the colorimetric reaction of the in vitro chemosensitivity test: MTT assay.

We compared the colorimetric reactions between the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl 2H-tetrazolium bromide (MTT) assay and the succinate dehydrogenase inhibition (SDI) test, in order to evaluate the usefulness of the SDI test for in vitro chemosensitivity testing. The addition of sodium succinate enhanced the colorimetric absorbance at 565 nm in the MTT assay in a dose- and a time-dependent manner, in mouse sarcoma-180 (S-180) cells. At 10 microM of sodium succinate, a dose used in the SDI test, the absorbance of the MTT assay increased by about 2.5-fold in the S-180 cells and in 10 human tumor tissues. The absorbance in the SDI test correlated well with the viable cell number of S-180 cells (r = 0.9993). These results show that the SDI test, using MTT as a tetrazolium salt, has a higher sensitivity for predicting cell viability, compared to the MTT assay.

Animals↗
PubMed1988

UFT is more antineoplastic against gastric carcinoma than 5-fluorouracil, 1-(2-tetrahydrofuryl)-5-fluorouracil and 1-hexylcarbamoyl-5-fluorouracil.

The sensitivity of human gastric cancer tissue to 5-fluorouracil (5-FU) and its analogues 1-(2-tetrahydrofuryl)-5-fluorouracil (FT), UFT and 1-hexylcarbamoyl-5-fluorouracil (HCFU) was determined, using the in vivo subrenal capsule (SRC) assay. The relative variation of tumor size (delta TS/TS0) was calculated as follows: delta TS/TS0 = (TS6-TS0/TS0) x 100%, where TS6 was the tumor size on day 6 and TS0 on day 0. The chemosensitivity was considered to be positive when delta TS/TS0 in the treated group decreased to below -10%. For their cytotoxic effects, 5-FU analogues are converted to 5-FU and positive correlations were noted between the tumor sizes of 5-FU and its analogues (5-FU vs. FT, r = 0.737; 5-FU vs. UFT, r = 0.653; 5-FU vs. HCFU, r = 0.709), in gastric tissues from 22 patients. The means +/- SD of tumor size were -8.5 +/- 11.5% for 5-FU, -8.3 +/- 16.0% for FT, -18.1 +/- 15.8% for UFT and -13.7 +/- 13.4% for HCFU. Decrease in tumor size was marked in case of exposure to UFT, compared with that to 5-FU (p less than 0.001), FT (p less than 0.001) and HCFU (p less than 0.05). 18% were sensitive to UFT and resistant to 3 other drugs. Thus, UFT proved to be the most effective among 5-FU and its analogues for decreasing the size of gastric cancer tissues.

Animals↗
PubMed1988

[Human colorectal carcinoma is more sensitive to HCFU than 5-FU and tegafur in in vitro and in vivo drug sensitivity tests].

The sensitivity of human colorectal cancer to 5-fluorouracil (5-FU) and its derivatives: 1-(tetrahydro-2-furyl)-5-FU (tegafur) and 1-hexylcarbamoyl-5-FU (HCFU) was determined by in vitro succinate dehydrogenase inhibition (SDI) test and in vivo subrenal capsule (SRC) assay. Using the SDI test with 25 colorectal cancer specimens, the succinate dehydrogenase (SD) activity decreased to 73.6 +/- 17.8% for 5-FU-treated cells and 37.2 +/- 17.0% for HCFU-treated cells, compared to that of control cells. The chemosensitivity-positive rates were 16% for 5-FU and 68% for HCFU. Using the SRC assay with 7 colorectal cancer specimens, the relative variation of tumor size, which was calculated by delta TS/TS0 = (TS6-TS0)/TS0 X 100 (%), decreased to -12.6 +/- 10.1% for 5-FU, -14.9 +/- 12.4% for tegafur and -23.9 +/- 14.2% for HCFU, and the inhibition of tumor growth following exposure to HCFU was evident. The chemosensitivity-positive rates were 49% for 5-FU, 57% for tegafur and 71% for HCFU. Our results show that HCFU is more effective to colorectal cancer than 5-FU and FT-207, and the chemosensitivity test of HCFU will be useful in determining the effective drug for the treatment of colorectal cancer.

Animals↗
PubMed1988

Chemosensitivity differences between primary and metastatic lesions of clinical gastric cancer.

An in vitro chemosensitivity test, the succinate dehydrogenase inhibition (SDI) test, was used to examine 16 pairs of samples obtained simultaneously from primary and metastatic lesions of clinical gastric cancer. Concerning the metastases, 11 were in the lymph nodes and five in the liver. The chemosensitivities of metastatic lesions against six anti-tumour drugs, carboquone (CQ), adriamycin (ADM), mitomycin C (MMC), aclacinomycin A (ACR), and 5-fluorouracil (5-FU), differed from those in the primary lesions, and there were no correlations of chemosensitivities between the primary and the metastatic lesions against these drugs, except for DDP. The lymph nodes were more sensitive to CQ, ADM, MMC, DDP, ACR and 5-FU, while the liver was less sensitive than the primary lesions to CQ, ADM, MMC, DDP, and ACR. Our findings indicate that in patients with lymph node metastasis, there is a sensitivity to anti-tumour drugs, while in cases of liver metastasis, drug treatment may be less effective. We propose that chemosensitivity testing should be done when attempting to design anti-tumour drugs.

Antineoplastic Agents↗
PubMed1987

1-Hexylcarbamoyl-5-fluorouracil is more cytostatic than 5-fluorouracil against human tumors in vitro.

The sensitivity of HeLa cells and 15 human tumors, including eight gastric cancers, five colorectal cancers and two lung cancers to 1-hexylcarbamoyl-5-fluorouracil (HCFU) was compared with that to 5-fluorouracil (5-FU) in vitro. HeLa cells were doubly sensitive to HCFU, as compared to 5-FU. After the HeLa cells had been treated with 5-FU or HCFU at 77 microM for 1-5 h, the intracellular levels of 5-FU and HCFU were determined, using gas chromatographic-mass spectrometric methods. The level of HCFU plus 5-FU in the HCFU-treated cells was twice as high as the level of 5-FU in the 5-FU-treated cells. The sensitivity to HCFU in 15 tumor tissues varied with the tissue; however, all tissues tested were more sensitive to HCFU than to 5-FU, assessed using the succinate dehydrogenase inhibition test. These results suggest that the hexylcarbamoyl structure facilitates the rapid uptake of HCFU through the cell membrane. HCFU may prove to be more effective for treating each individual patient with a malignant lesion.

Antineoplastic Agents↗