Biomedical subjects

N Oya

Publications and source records attributed to N Oya.

At least 37 records · Page 2Linked to original sources

PubMed2000

Enhanced cell killing by overexpression of dominant-negative phosphatidylinositol 3-kinase subunit, Deltap85, following genotoxic stresses.

Phosphatidylinositol 3-kinase (PI3-K) is a heterodimer of a regulatory subunit, p85, and a catalytic subunit, p110. A number of previous reports showed that PI3-K functions in diverse cellular phenomena such as cell proliferation, glucose catabolism, cell adhesion, and vesicle transport. It is also well known that a survival signal from the receptor tyrosine kinases utilizes Akt via PI3-K to protect cells from apoptosis. To examine the role of PI3-K in cellular sensitivity to genotoxic stresses such as cisplatin and ultraviolet (UV), we introduced deletion type p85 (Dp85) into two human glioblastoma cell lines (T98G and A172) and one melanoma cell line (G361). The Deltap85 works in a dominant-negative fashion on PI3-K activity by disrupting its p85 / p110 interaction. In all three transfected cell lines, the overexpression of Deltap85 rendered the cells markedly more sensitive to these DNA-damaging stresses than the cells transfected with the vector alone. Apoptosis was vigorously induced in cells overexpressing Dp85 following the treatment. The present results imply that PI3-K plays a critical role in determining cellular sensitivity to genotoxic stresses in human cancer cells, and that disruption of the p85 / p110 interaction of PI3-K may be a potential molecular target for developing a novel strategy for cancer treatment.

Apoptosis↗

PubMed1999

Biochemical examination of mother's urine is useful for prenatal diagnosis of Bartter syndrome.

Bartter syndrome is characterized by renal potassium and chloride loss, hypokalaemia, hypochloraemic metabolic alkalosis and increased plasma renin activity along with elevated angiotensin II and hyperaldosteronism. For diagnosis we conducted biochemical examinations of both amniotic fluid and the mother's urine. Except for potassium, amniotic fluid electrolytes in a mother with a fetus with Bartter syndrome were high. Urinary chloride, sodium and calcium were very low. Thus, the latter parameters may allow prediction of fetal Bartter syndrome during the prenatal period.

Adult↗

PubMed1999

A case of successful conservative chemotherapy for intramural pregnancy.

OBJECTIVE: To describe a rare case of intramural pregnancy diagnosed with the use of magnetic resonance imaging (MRI) and conservatively managed. DESIGN: Case report. SETTING: Department of obstetrics and gynecology in a university hospital. PATIENT: A 33-year-old healthy patient with a history of a partial mole after 3 years of primary unexplained infertility. INTERVENTION(S): Laparoscopic and transvaginal local injections of methotrexate. MAIN OUTCOME MEASURE(S): Transvaginal ultrasound (US) and MRI findings. RESULT: Treatment was successful, with no complications, and the patient's reproductive potential was preserved. CONCLUSION(S): Early detection of intramural pregnancy with the use of transvaginal US is important, and MRI is a useful, noninvasive imaging modality. Chemotherapy with methotrexate is an effective treatment that allows preservation of reproductive potential.

Adult↗

PubMed1999

Systemic chemotherapy with vincristine, cyclophosphamide, doxorubicin and prednisolone following radiotherapy for primary central nervous system lymphoma: a phase II study.

We treated 23 patients with primary central nervous system lymphoma with a protocol of conventional radiation up to 55 +/- 5 Gy followed by 4 to 6 cycles of intravenous doxorubicin (30 mg/m2), vincristine (1 mg/m2) and cyclophosphamide (350 mg/m2), and oral prednisolone (8-30 mg/m2) (VEPA chemotherapy) repeated at 2-week intervals. The median age of the 23 patients was 59 years, and the median World Health Organization performance status score was 2. Seventeen patients received 4 or more courses of the chemotherapy, but 6 received only 1 or 2 courses for various reasons. The median survival time for all 23 patients was 25.5 months and their 5-year survival rate was 23%. These values were 34 months and 32%, respectively, for the 17 patients who received 4-6 courses of chemotherapy. After treatment, decline in performance status unaccompanied with tumor recurrence was observed in 44% of the patients; the incidence was apparently higher in older than in younger patients. The survival results obtained with this combined radiochemotherapy regimen appear to be better than those reported in most previous studies of patients treated with radiation alone. Post-irradiation VEPA chemotherapy appears to be worthy of further evaluation.

Adult↗

PubMed1999

A significant correlation between clonogenic radiosensitivity and the simultaneous assessment of micronucleus and apoptotic cell frequencies.

PURPOSE: To study the relationship between clonogenic radiosensitivity and a simultaneous assessment of the percentages of radiation-induced micronuclei (MN) and apoptotic cells. MATERIALS AND METHODS: Five mammalian cell lines were studied. Following irradiation, measurements were made of the percentages of MN, apoptotic cells and floating cells. Each factor was compared, both alone and as the simple sum of the factors, with cell survival. The factors were also evaluated using a multiple linear regression analysis. RESULTS: The simple sum of the MN and apoptotic cell percentages, the sum of the MN and floating cell percentages, and the sum of all three factors correlated with cell survival. However, the multiple linear regression analysis was the best method of predicting cell survival. CONCLUSIONS: These results suggest the usefulness of the simultaneous assessment of the MN frequency and the detection of floating cells in culture medium or apoptotic cells among attached cells to predict cellular intrinsic radiosensitivity. In order to predict cell survival after irradiation from these factors, the use of multivariate analyses is more useful than simple summation.

Animals↗

PubMed1998

Effects of SN-38 (an active metabolite of CPT-11) on responses of human and rodent cells to irradiation.

PURPOSE: Modulators of the DNA-unwinding enzyme, topoisomerase I (Topo I), inhibit DNA repair and have been reported to increase the lethal effects of X rays, which create breaks in DNA. CPT-11 is a derivative of camptothecin, a Topo I inhibitor, and is clinically available. In this study, we tested the in vitro combination effects of SN-38, an active form of CPT-11, and irradiation on several cell lines. MATERIALS AND METHODS: Exponentially growing or confluent cultures of CHO cells were treated with SN-38 for 30 min. Cells were then irradiated. Thereafter, the cells were further incubated with the drug for 0 to 3 h. Exponentially growing other cell lines were exposed to 200 nM SN-38 for 30 min before, during, and 3 h after irradiation. The cell survival rate was determined using a conventional clonogenic assay. RESULTS: SN-38 (200 nM to 4 microM) alone showed slight toxicity to CHO cells in the confluent culture after a 3.5-h incubation. When the cells were treated with the lower doses of SN-38 (50 to 800 nM) during the exponentially growing phase, the cell survival rates were much lower. In combination with irradiation, SN-38 showed only additive effects to irradiation when cells were treated in confluent cultures. However, higher combination effects of SN-38 and irradiation were observed in the cells treated in the exponentially growing phase. When cells were irradiated during the exponentially growing phase, a significant combination effect of 200 nM SN-38 and irradiation was also observed in some cell lines, but not in others. CONCLUSION: SN-38 and irradiation showed supraadditive effects in some cell lines, when treated in the exponentially growing phase, but not in other cell lines or when cells were treated in the confluent phase.

Animals↗

PubMed1998

The influence of DNA ploidy of a human tumor cell line on the frequencies of micronuclei or chromosome aberrations after irradiation.

To develop methods for assessing the intrinsic cellular radiosensitivity, it is important to evaluate the relationship between DNA ploidy of cells and frequencies of micronuclei (MN) or chromosome aberrations after irradiation. From the original human fibrosarcoma cell line HT-1080, we isolated two clones which have different chromosome ploidy: clone 5 is pseudodiploid and clone 1 is heteroploid. We examined the radiosensitivity of the two clones using a clonogenic cell survival assay and a cytokinesis-block MN assay, and by scoring chromosome aberrations using the premature chromosome condensation (PCC) method combined with a fluorescence in situ hybridization (FISH) procedure immediately and at 24 h after irradiation. The MN frequency increased according to the irradiation dose in both clones. The MN frequency of clone 1 was significantly higher than that of clone 5 regardless of whether the assay was performed immediately or 24 h after irradiation. However, when the numbers of MN were normalized by the DNA index of each clone, a significant difference in the frequency of MN was not observed. In the PCC and FISH studies, there was a linear relationship between the radiation dose and the initial breaks of chromosome 4, but the breaks of clone 1 were much more frequent than those of clone 5. Twenty-four h after irradiation, the chromosome 4 breaks of clone 1 were observed much more frequently than those of clone 5 at the same radiation dose. When the numbers of chromosome 4 breaks were normalized by the number of chromosome 4 in each clone without radiation, no such difference in the number of breaks was observed. These findings demonstrated that the DNA content or chromosome ploidy influenced the induction of the MN or chromosome aberrations in HT-1080 cells after irradiation.

Cell Survival↗

PubMed1998

Simultaneous evaluation of radiation-induced apoptosis and micronuclei in five cell lines.

PURPOSE: This study was conducted to clarify the relationship among the frequencies of micronuclei (MN) and apoptosis, and clonogenic cell survival after irradiation. MATERIALS AND METHODS: The frequencies of MN and apoptosis were compared in the surviving fraction in three human tumour cell lines and two rodent cell lines at various irradiation doses. RESULTS: The SHIN-3, DU-145 and CHO-K1 cells showed dose-dependent increases of MN per binucleate cell and an excellent correlation between the MN frequency and surviving fraction after irradiation. The F9 and COLO 320DM cells did not show this correlation. The number of apoptotic cells increased according to the increase in radiation dose in the F9 and COLO 320DM cells, but not in the SHIN-3, DU-145 or CHO-K1 cells. CONCLUSIONS: The detection of the MN frequency alone is insufficient to measure cellular intrinsic radiosensitivity. The simultaneous use of the MN assay and the detection of apoptotic cells would be more reliable as a method for predicting cell survival after radiation.

Animals↗

PubMed1998

Minute chromosomal rearrangements detected prenatally by fluorescence in situ hybridization.

Initial approaches to prenatal diagnosis from fetal karyotyping involved application of standard cytogenetic techniques. However, when fetal samples, such as chorionic villus cells or amniocytes are used, small chromosome rearrangements cannot be easily identified because they lack a distinct banding pattern. We report here two cases with minute chromosome rearrangements detected prenatally by fluorescence in situ hybridization. The use of this technique allowed precise identification of fetal chromosome abnormalities, demonstrating its usefulness for characterizing conditions that would be difficult to diagnose correctly with conventional banding methods alone.

Adult↗

PubMed1997

[MR spectroscopy in acute brain infarction: differentiation of infarcted and non-infarcted areas].

Two cases of brain infarction were studied using multivoxel proton MR spectroscopy (MRS). MRS of both cases clearly demonstrated an increased level of lactate and decreased N-acetylaspartate (NAA), resulting in a high lactate/NAA ratio (LNR). Case 1 without thrombolysis therapy revealed that the area where LNR was less than 1.0 did not develop to infarction. This was also confirmed by MRS of case 2, who received an interventional reperfusion 4 hours after onset. In acute stags of brain infarction, on LNR greater than 1.0 on H-MRS may predict the margin of the infarcted region. Elevation of lactate in the non-infarcted cerebral hemisphere has not been reported before, and farther evaluation is necessary.

Aspartic Acid↗

PubMed1996

Reoxygenation after single irradiation in rodent tumors of different types and sizes.

PURPOSE: To investigate the variation of reoxygenation patterns after single irradiation in murine tumors of different types and sizes. METHODS AND MATERIALS: Whole-body single irradiation of 13 to 15 Gy was delivered to 10 mm RIF1 tumors of C3H/He mice, 22 mm SCCVII tumors of C3H/He mice, and 16 mm EMT6 tumors of Balb/c mice. Thereafter, changes in the hypoxic fraction with time were determined by the paired survival curve method. The data were compared with the results we had ++previously obtained with 10 mm SCCVII and 10 mm EMT6 tumors. RESULTS: The hypoxic fraction at 1 h after the priming irradiation was 26% for 10 mm RIF1 tumors, 48% for 10 mm SCCVII tumors, and 100% for 10 mm EMT6 tumors. Thus, RIF1 and SCCVII tumors, both of which have few necrotic areas, showed rapid reoxygenation, whereas EMT6 tumors, which have large necrotic areas, reoxygenated slowly. Although the hypoxic fraction returned to the pretreatment level within 72 h in 10 mm SCCVII and 10 mm EMT6 tumors, it did not in 10 mm RIF1 tumors. In contrast, the patterns of reoxygenation were similar between 22 mm and 10 mm SCCVII tumors and between 16 mm and 10 mm EMT6 tumors. CONCLUSION: The three tumors showed different patterns of reoxygenation. Tumors that have a low proportion of necrosis may reoxygenate rapidly. However, tumor size appeared to have less influence on the pattern of reoxygenation.

Animals↗

PubMed1996

Combined effect of clinically relevant doses of emitefur, a new 5-fluorouracil derivative, and radiation in murine tumours.

We investigated the combined effect of radiation and clinically relevant doses of emitefur (BOF-A2), a newly developed anti-cancer agent consisting of a masked form of 5-fluorouracil (5-FU) and a potent inhibitor of 5-FU degradation, in two types of murine tumours. In preliminary pharmacokinetic studies, the area under the curve for 5-FU in plasma, after administration of 12.5 mg kg-1 and 25 mg kg-1 emitefur in mice, appeared to be similar to that obtained on the first day and that on the seventh day, respectively, after starting administration of 400-600 mg day-1 in humans. These doses (12.5 and 25 mg kg-1) of emitefur were evaluated either alone or in combination with single (15 Gy), five-fraction (4 Gy each) or ten-fraction (2.8 Gy each) irradiation using a tumour growth delay assay for SCCVII tumours and in combination with four-fraction (5 Gy each) irradiation using an in vivo-in vitro assay for EMT6 tumours. The anti-tumour and radiation-enhancing effects of 12.5 mg kg-1 emitefur were not significant in any except the ten-fraction experiment. On the other hand, multiple doses of 25 mg kg-1 emitefur given either alone or in combination with radiation produced marked effects. The mean tumour growth delay time (the time to double in volume for treated tumours minus that for untreated tumours) was 8.1 days for five administrations of 25 mg kg-1 emitefur. 10.4 days for five fractions of 4 Gy and 22.1 days for five treatments with the combination of the two. Thus, the increase in growth delay afforded by this combination was at least additive. The effect of four fractions of 5 Gy with 25 mg kg-1 emitefur in EMT6 tumours was lower than that of four fractions of 7.5 Gy, but the effect of five fractions of 4 Gy with this dose of emitefur in SCCVII tumours was similar to the effect of five fractions of 6 Gy, and the effect of ten fractions of 2.8 Gy with 25 mg kg-1 emitefur was much higher than that of ten fractions of 4.2 Gy. In conclusion, emitefur given either alone or in combination with radiation appears to have a significant anti-tumour effect even at clinically relevant dose levels, although a threshold dose exists between 12.5 and 25 mg kg-1. Further clinical studies of this compound are warranted.

Animals↗

PubMed1996

Comparison of in vivo efficacy of hypoxic cytotoxin tirapazamine and hypoxic cell radiosensitizer KU-2285 in combination with single and fractionated irradiation.

Development of strategies to eradicate radioresistant hypoxic cells would be of great benefit for clinical radiotherapy. In the present study, the in vivo effects of a promising hypoxic cytotoxin, tirapazamine (3-amino-1,2,4-benzotriazine 1,4-di-N-oxide), were examined in comparison with those of KU-2285, one of the best hypoxic cell radiosensitizers, in combination with both single and fractionated irradiation. The tumor response was assessed by the standard in vivo-in vitro clonogenic assay using SCCVII tumors in C3H mice and EMT-6/KU tumors in Balb/c mice with different characteristics of tumor hypoxia. With single-dose irradiation (18 Gy), both tirapazamine and KU-2285 showed significant enhancement of cell killing in a dose-dependent manner, but tirapazamine was more effective for SCCVII tumors with acutely hypoxic cells, while KU-2285 was more effective for EMT-6/KU tumors predominantly with chronically hypoxic cells. In fractionated irradiation regimens (4 fractions of 5 Gy at 12 h intervals), tirapazamine showed more marked combined effects at 10 and 20 mg/kg than KU2285 at 100-200 mg/kg in both SCCVII and EMT-6/KU tumors. We concluded that the effectiveness of KU-2285 and tirapazamine was correlated with the nature of tumor hypoxia with single-dose irradiation, whereas tirapazamine appeared more potent than KU-2285 with fractionated irradiation. These findings suggest the potential usefulness of tirapazamine in clinical fractionated radiotherapy.

Animals↗

PubMed1996

FDG-PET evaluation of therapeutic effects on VX2 liver tumor.

UNLABELLED: Transplanted VX2 liver tumor in the rabbit is an experimental liver tumor model in which 18F-2-fluoro-2-deoxy-D-glucose (FDG) accumulates to a 3.5-fold level that surrounds normal liver tissue. In this study, changes in FDG uptake were assessed in this liver tumor model after transcatheter arterial embolization (TAE) and radiotherapy. METHODS: Fifteen rabbits bearing VX2 liver tumors were treated with TAE with gelatin sponges 1 day before the FDG study, and 18 rabbits received local irradiation with electron beams at a dose of 12-36 Gy 1-10 days before the FDG study. In the FDG study, serial arterial blood sampling was performed to determine arterial input (AI), and 1 hr after tracer injection, normal liver tissue and tumor tissue were excised to measure radioactivity. The tumor FDG level per AI and the tumor-to-normal liver ratio were assessed. Dynamic PET images were obtained in 20 of the 46 rabbits. RESULTS: Tumor FDG uptake was significantly decreased 1 day after TAE (from 3.54 to 0.83 in the tumor-to-normal liver ratio) and 5 days after 30 Gy of irradiation (from 3.54 to 1.28). The decrease in tumor FDG uptake was dose-dependent, especially in the relatively low dose range (12-24 Gy). The untreated tumors could be clearly distinguished from the surrounding normal liver tissue, while the embolized tumors or the irradiated tumors were not clearly delineated. Histological analysis showed that the decrease in tumor FDG after treatment agreed well with the decrease in number of viable tumor cells. CONCLUSION: The VX2 liver tumor is an appropriate experimental tumor model for evaluating the change in FDG uptake in various therapeutic modalities. Moreover, the therapeutic effects can be assessed 1 day after TAE and 5 days after irradiation. Further clinical trials for the early evaluation of therapeutic effects on liver tumors using FDG-PET are warranted.

Animals↗

PubMed1996

Tirapazamine: hypoxic cytotoxicity and interaction with radiation as assessed by the micronucleus assay.

We investigated the cytotoxicity and the interaction with low-dose radiation (1-4Gy) of tirapazamine by the in vitro cytokinesis-block micronucleus (MN) assay. Murine SCCVII and human melanoma (G-361) cells were treated with tirapazamine under aerobic or hypoxic conditions for 1 h and the MN frequency was determined using cytochalasin-B. The cells were also treated with or without tirapazamine or KU-2285 (hypoxic cell sensitiser) under hypoxic conditions and irradiated with or without reaeration of the cell suspensions. A dose-dependent increase of MN frequency was observed by tirapazamine treatment and the hypoxic toxicity ratio was about 130 for SCCVII and 37 for G-361. The radiation dose-response curves of MN frequency suggested that the interaction of tirapazamine with irradiation appeared to be essentially additive in both cell lines. In contrast, the dose-response curve became steeper by KU-2285 treatment. Combined effects of tirapazamine and irradiation on the hypoxic cells were much higher than the radiation effect on aerobic cells at low doses, while the effects of KU-2285 did not exceed that of aerobic irradiation. In conclusion, tirapazamine appeared to be superior to hypoxic radiosensitisers at clinically relevant doses, not because of aerobic radiosensitisation but because of its potent hypoxic cytotoxicity additive to radiation effect.

Animals↗

PubMed1996

The combined antitumour effect of a new 5-fluorouracil derivative, BOF-A2, and radiation in vivo.

We examined the combined effect of radiation and BOF-A2, a newly developed anti-cancer agent consisting of a masked form of 5-fluorouracil (5-FU) and a potent inhibitor of 5-FU degradation in the liver, on murine tumors. Subcutaneous 8-mm-diameter SCCVII tumours grown in the right thigh of C3H/He mice were used. The mice were locally irradiated with single doses of 10-30 Gy or five fractions of 4 Gy for 5 days, alone or in combination with BOF-A2. BOF-A2 at doses of 30, 75 and 150 mg kg-1 was orally administered 2 h before or immediately after single doses of irradiation, while 15 or 30 mg kg-1 of BOF-A2 was given 1 h prior to each fraction of 4 Gy. The effect of BOF-A2 alone was also examined. The antitumour effect was evaluated by a tumour growth delay assay. BOF-A2 alone showed significant tumour growth delay at all doses used in this study. Combination of BOF-A2 and single or fractionated doses of radiation appeared to produce an additive tumour response, which occurred independently of sequence of the two treatments. The combined effect became greater with the dose of radiation and BOF-A2. In conclusion, BOF-A2 and radiation may be efficiently combined.

Animals↗

PubMed1995

Optical isomers of a new 2-nitroimidazole nucleoside analog (PR-350 series): radiosensitization efficiency and toxicity.

PURPOSE: A new 2-nitroimidazole nucleoside radiosensitizer, PR-350 (1-[1',3',4'-trihydroxy-2'-butoxy]-methyl-2-nitroimidazole), has been reported to be as efficient as and less toxic than etanidazole. This compound is racemic, and it was recently optically resolved into two isomers, PR-68 (2'R,3'S type) and PR-69 (2'S,3'R type). The other two isomers, PR-28 (2'S,3'S type) and PR-44 (2'R,3'R type), were asymmetrically synthesized. In the present study, we investigated the properties, sensitizing activity, and toxicity of PR-350 and the four optical isomers in comparison with those of other 2-nitroimidazole hypoxic cell radiosensitizers, etanidazole, KU-2285, KIN-804, and RP-170. Because PR-350 and PR-28 can be industrially synthesized, we evaluated whether either of these two drugs are suitable for further investigation. METHODS AND MATERIALS: In an in vitro study, EMT-6 cells were irradiated at a dose of 1-3 Gy under hypoxic conditions in the presence of the drugs at a concentration of 1 mM. A combined cytokinesis-block micronucleus and chromosomal aberration assay was performed. To assess the in vivo effects, colony assay and growth delay assay were performing using SCCVII tumor-bearing C3H mice. The mice received 16-24 GY 10-40 min after administration of 50-200 mg/kg of the drugs. Toxicity and pharmacokinetics in mice were also investigated. RESULTS: The sensitizer enhancement ratio (SER) in the in vitro cytokinesis-block micronucleus assay increased in the following order: PR-69 (1.27) approximately equal to PR-28 (1.31) approximately equal to PR-44 (1.38) approximately equal to PR-350 (1.41) approximately equal to PR-68 (1.47) < etanidazole (1.79) < KIN-804 (2.03) approximately equal to KU-2285 (2.30). The SER at a dose of 200 mg/kg and at an interval of 20 min (optimal interval) in the in vivo-in vitro colony assay increased as follows: PR-44 (1.26) approximately equal to PR-28 (1.29) < PR-69 (1.34) approximately equal to etanidazole (1.35) approximately equal to PR-350 (1.36) < RP-170 (1.41) approximately equal to PR-68 (1.41) < KU-2285 (1.49). The growth delay assay also showed that PR-350 was less efficient than KU-2285 and more efficient than PR-28. PR-350 and the four isomers had similar reduction potentials, but PR-28 and PR-44 were more hydrophilic than PR-68 and PR-69. The LD50 in mice were 5.8 g/kg for PR-350, approximately 7 g/kg for PR-28, 4 g/kg for PR-68, and 6 g/kg for PR-44 and PR-69. The concentration of PR-28 in the murine sciatic nerve was lower than that of PR-350. CONCLUSION: In vivo radiosensitizing activity differed among the four optical isomers, which appeared to be due, at least in part, to differences in lipophilicity. Although PR-28 was the least toxic, its low sensitization efficiency does not warrant clinical trials. Among the PR compounds, PR-68 appears to be most efficient, but optical resolution of PR-68 from PR-350 is expensive, and asymmetrical synthesis of PR-68 is not established. Therefore, PR-350 seems to be most suitable for further investigation among the PR-350 series compounds, considering its higher efficiency compared with PR-28 and PR-44, and established synthesis.

Animals↗

PubMed1995

Assessment of micronucleus induction in SCCVII cells treated with bioreductive agents, WIN 59075 (SR 4233) and mitomycin C, under aerobic and hypoxic conditions.

WIN 59075 (SR4233, tirapazamine) is a promising bioreductive antitumor agent preferentially more toxic to hypoxic cells and presently undergoing phase I clinical trials. In this investigation, we have examined the applicability of the cytokinesis-block micronucleus assay to assess the effects of bioreductive agents. SCCVII tumor cells were treated with WIN 59075 or mitomycin C at various concentrations under aerobic and hypoxic conditions. Significant induction of micronuclei in binucleate cells was demonstrated in a dose-dependent fashion and it appeared to be strongly correlated with the loss of clonogenicity in the colony assay. Both agents showed selectively higher toxicity to hypoxic cells than to aerobic cells and the ratios of the concentrations required to obtain the equivalent effects under aerobic and hypoxic conditions could be also estimated by this method as follows: the hypoxic toxicity ratios were 120-130 for WIN 59075 and 3.0-3.3 for mitomycin C. For several favorable characteristics, the cytokinesis-block micronucleus assay can provide an alternative, rapid, and reproducible means for evaluation of antitumor activities from chromosomal breakage caused by the bioreductive agents.

Dose-Response Relationship, Drug↗