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Biomedical subjects

Y Shibamoto

Publications and source records attributed to Y Shibamoto.

At least 91 records · Page 5Linked to original sources
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↗
PubMed1996

Kyoto University experience with intraoperative radiation therapy.

To date, intraoperative radiotherapy has been performed at Kyoto University Hospital in a total of 480 patients with malignancies various sites. Among these, patients with disease of 4 major sites were selected for prognostic analysis. For gastric cancer patients survival was improved by the adjuvant intraoperative radiotherapy compared with gastrectomy alone in those with advanced nodal or serosal involvement [P < 0.05 for n2 + n3' 0.1 > P > 0.05 for s(+)]. Also, the survival for the adjuvant radiotherapy group was significantly improved in patients with stage II-III pancreatic cancer who underwent non-curative resection (P < 0.001). For patients with soft tissue sarcomas of the extremities, intraoperative radiotherapy was performed after the tumours were surgically removed to the greatest e* possible. Operation curability had a great impact on the local tumour control rate (82% for curative resection versus 18% for non-curati resection) and on the long-term survival rates (65% versus 8%, respectively). In patients with osteosarcoma, a large single do* 50-55 Gy was applied to the affected limb in an attempt to achieve local control and limb salvage. By this method, good local control attained, and a 10-year survival rate showed improvement following the introduction of cisplatinum into intensive chemotherapy.

Bone Neoplasms↗
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↗
PubMed1995

Pre-treatment prognostic factors in patients with stage III non-small cell lung cancer treated with hyperfractionated radiation therapy with or without concurrent chemotherapy.

We analyzed prognostic factors for non-small cell lung cancer (NSCLC) treated with hyperfractionated radiotherapy (HFX RT) with or without concurrent chemotherapy. One-hundred sixty-nine patients with histologically or cytologically proven, Stage III NSCLC, Karnofsky performance status (KPS) > or = 50, and no previous therapy were treated in a randomized trial as follows: Group 1--HFX RT to a total dose of 64.8 Gy (61 patients); Group 2--the same HFX RT with chemotherapy consisting of 100 mg of carboplatin on days 1 and 2 and 100 mg of etoposide on days 1-3 of each week during the RT course (52 patients); and Group 3--the same HFX RT with chemotherapy consisting of 200 mg of carboplatin on days 1 and 2 and 100 mg of etoposide on days 1-5 of the first, third, and fifth weeks of the RT course (56 patients). The median survival time for all 169 patients was 13 months and the 5-year survival rate was 13.4%. The median time to relapse (local or distant) was 11 months and the 5-year relapse-free survival was 12.8%. Group 2 patients had a better prognosis than Group 1 patients (P = 0.0028) but there were no differences in prognosis between Groups 2 and 3 and between Groups 1 and 3. Of potential prognostic factors examined, female gender (P = 0.00012), age > or = 60 (P = 0.00000), KPS > or = 80 (P = 0.00000), Stage IIIA (P = 0.00000), and previous weight loss < or = 5% (P = 0.00000) were associated with better prognosis. These findings were confirmed by multivariate analysis.

Adult↗
PubMed1995

Accelerated hyperfractionated radiation therapy for malignant glioma. A phase II study.

Sixty-four adult patients with malignant glioma entered into a Phase II study on the use of accelerated hyperfractionated radiation therapy. Histology included anaplastic astrocytoma (AA) in 15 patients and glioblastoma multiforme (GBM) in 49 patients. Treatment consisted of radiation therapy doses of 66 Gy in 44 fractions in 22 treatment days in 4.5 weeks, fractions of 1.5 Gy, b.i.d. 1,3-bis(2-chlorethyl)-1-nitrosourea (BCNU) 80 mg/m2 and hydroxyurea 800 mg/m2 were both given on treatment days 1, 6, 11, 16, and 21 during the irradiation course. Median survival time for all 64 patients is 61 weeks (range; 12-163 weeks) from the date of starting irradiation. Median time to tumor progression (MTP) for GBM patients is 31 weeks, and 1-year and 3-year progression-free survival (PFS) are 16% and 0%, respectively, while MTP for AA patients is not attained yet, and 1-year and 3-year PFS are 100% and 73%, respectively. On univariate analysis of prognostic factors for GBM patients, younger age, total or subtotal tumor removal, and frontal tumor location are associated with a better prognosis. A multivariate analysis confirmed the importance of the extent of surgery and tumor site and revealed the interfraction interval (4.5-5.0 hours vs 5.5-6.0 hours, p = .041) as an important prognostic factor. Acute and late toxicity is not increased. Longer follow-up and more patients are needed to evaluate tumor control and toxicity in AA patients.

Adult↗
PubMed1995

Randomized trial of hyperfractionated radiation therapy with or without concurrent chemotherapy for stage III non-small-cell lung cancer.

PURPOSE: To investigate the efficacy of combined hyperfractionated radiation therapy (HFX RT) and concurrent chemotherapy (CHT) in stage IIIA or IIIB non-small-cell lung cancer (NSCLC) compared with that of HFX RT alone. PATIENTS AND METHODS: Between January 1988 and December 1989, 169 patients were divided randomly into the following groups: group I, HFX RT with 1.2 Gy twice daily to a total dose of 64.8 Gy (n = 61); group II, same HFX RT with CHT consisting of 100 mg of carboplatin (CBDCA) on days 1 and 2 and 100 mg of etoposide (VP-16) on days 1 to 3 of each week during the RT course (n = 52); and group III, same HFX RT with CHT consisting of 200 mg of CBDCA on days 1 and 2 and 100 mg of VP-16 on days 1 to 5 of the first, third, and fifth weeks of the RT course (n = 56). RESULTS: The median survival time (MST) was 8 months for group I, 18 months for group II, and 13 months for group III. The 3-year survival rates were 6.6%, 23%, and 16%, respectively. There was a significant difference in the survival rate between groups I and II (P = .0027, log-rank test), but not between groups I and III (P = .17) or between groups II and III (P = .14). The relapse-free survival rate in group II was also higher than that in group I (P = .0024), which was largely due to improved local control in group II patients. Patients in groups II and III showed a higher incidence of acute and/or late high-grade toxicity compared with group I patients, but no patient died of treatment-related toxicity. CONCLUSION: The combination of HFX RT and continuous CBDCA/VP-16 CHT was tolerable and substantially increased the survival rate.

Adult↗
PubMed1994

The effects of intraoperative radiotherapy on bone-healing ability in relation to different doses and postradiotherapy intervals.

PURPOSE: Alterations in bone-healing ability after intraoperative radiotherapy were investigated in relation to different doses and postradiotherapy intervals in an experimental model. METHODS AND MATERIALS: Bilateral osteotomy of the fibulae of 56 rabbits was carried out either immediately, 13 weeks or 39 weeks after unilateral intraoperative radiotherapy with 10-MV X ray using one of three doses, 25, 50, or 100 Gy. The healing of the fibulae was evaluated radiographically and histologically 13 weeks after the osteotomy. RESULTS: Bone-healing ability was irreversibly reduced in all irradiated fibulae and these damages occurred in a dose-dependent manner. The severity of the damage also tended to increase with the time interval between irradiation and osteotomy. This interval-related aggravation was characterized by augmented bone loss at the osteotomy ends and atrophy of the neighboring areas. CONCLUSION: These results serve as useful information concerning the surgical intervention of irradiated bone during and after intraoperative radiotherapy, and also after conventional radiotherapy.

Animals↗
PubMed1994

Combined cytokinesis-block micronucleus and chromosomal aberration assay for the evaluation of radiosensitizers at low radiation doses.

PURPOSE: Several methods have been tried for evaluating the efficacy of hypoxic cell radiosensitizers at clinically relevant low radiation doses (1-4 Gy). The cytokinesis-block micronucleus assay is known to be useful for both the in vitro and in vivo evaluation of radiosensitizers, while the chromosomal aberration assay has been commonly used to assess the mutagenicity of various agents. In the present study, the chromosomal aberration assay and the cytokinesis-block micronucleus assay were performed simultaneously to assess the radiosensitizing effect of etanidazole and KU-2285 at low radiation doses. The correlation between the two assays was also evaluated. METHODS AND MATERIALS: In vitro study: EMT-6 cells were irradiated at a dose of 1-3 Gy under hypoxic conditions with or without the drugs at 1 mM. In vivo-in vitro study: EMT-6 tumor-bearing BALB/c mice received 2-4 Gy of radiation with or without administration of the drugs at 200 mg/kg. Single-cell suspensions were then obtained in both studies and were used for the cytokinesis-block micronucleus assay and the chromosomal aberration assay. The micronucleus frequency in binucleate cells was evaluated in the former assay, and the frequency of chromosomal aberrations in metaphase cells was evaluated in the latter assay. RESULTS: In vitro study: the sensitizer enhancement ratios of etanidazole and KU-2285 were 1.73 and 2.21, respectively, in the micronucleus assay, and 1.41 and 1.79 in the chromosomal aberration assay. In vivo-in vitro study: the sensitizer enhancement ratios of etanidazole and KU-2285 were 1.18 and 1.31, respectively, in the micronucleus assay, and 1.16 and 1.42 in the chromosomal aberration assay. In both studies, a linear correlation was observed between the micronucleus frequency and the chromosomal aberration frequency. The background (i.e., the frequency at 0 Gy) of the latter assay was considerably lower than that of the former assay, especially in the vivo study. CONCLUSIONS: The chromosomal aberration assay has not yet been established as a method for evaluating the effect of radiosensitizers. However, a combination of the cytokinesis-block micronucleus assay and the chromosomal aberration assay seems to be useful for assessing radiosensitizers at low radiation doses for the following reasons: a) the chromosomal aberration assay is as sensitive as the micronucleus assay and possibly more specific, because chromosomal aberrations can be observed before cells pass through the first metaphase after irradiation and, thus, reflect quite acute damage, even though they reflect only a part of the total damage; b) the combined assay provides relatively more information for the time and labor required.

Aerobiosis↗
PubMed1994

Hyperfractionated radiation therapy (HFX RT) followed by multiagent chemotherapy (CHT) in patients with malignant glioma: a phase II study.

PURPOSE: Forty-eight patients with malignant glioma were treated with hyperfractionated radiation therapy followed by multiagent chemotherapy to explore feasibility and toxicity of such combined modality treatment. METHODS AND MATERIALS: There were 34 males and 14 females with a median age of 53 years (range, 32-74 years) and median Eastern Cooperative Oncology Group performance status score of 1 (range, 0-3). Histology included anaplastic astrocytoma in 11 patients and glioblastoma multiforme in 37 patients. Radiation was given at 1.2 Gy per fraction, two fractions per day, for a total dose of 72 Gy, with a reduction in field size after 52.8 Gy. Four weeks after completion of hyperfractionated radiation therapy multiagent chemotherapy was introduced with bischlorethyl nitrosourea (BCNU) 50 mg/m2, days 1-3, vincristine 1.4 mg/m2 (max. 2 mg), day 1, procarbazine 50 mg/m2, days 1-7 and cisplatin 20 mg/m2, days 1-3. Cycles were repeated every 4 weeks to a maximum of six cycles or until tumor progression was noted. RESULTS: Median survival time for all patients was 52 weeks (range, 16-185 weeks) and median time to tumor progression was 30.5 weeks (range, 12-131 weeks). Besides age, histology, performance status, and extent of surgery, interfraction interval and location of tumor influenced survival in glioblastoma multiforms patients on univariate analysis: Patients treated with shorter intervals (4.5-5 h) did better than those treated with longer intervals (5.5-6 h); also, glioblastoma multiforme patients with frontal tumors did better than those with tumors of the other locations. Multivariate analysis confirmed that the performance status, interfraction interval, and tumor location were significant prognostic factors in glioblastoma multiforme patients. Acute toxicity was mild. No cases of brain necroses were observed. CONCLUSION: Hyperfractionated radiation therapy followed by multiagent chemotherapy was well tolerated with mild acute and virtually no late toxicity. More patients and longer follow-up are needed for further evaluation of its activity and late effects in anaplastic astrocytoma patients.

Adult↗
PubMed1994

The role of cerebrospinal fluid cytology in radiotherapy planning for intracranial germinoma.

PURPOSE: The association between the cerebrospinal fluid cytology findings and the clinical features of patients with intracranial germinoma was investigated to determine whether cerebrospinal fluid cytology could be helpful in determining the optimal radiation treatment volume. METHODS AND MATERIALS: Between 1976 and 1992, cerebrospinal fluid cytology was performed in 42 germinoma patients using a cytocentrifugation method. Forty patients received irradiation and 2 received chemotherapy with cisplatin and etoposide. RESULTS: Cerebrospinal fluid cytology was positive in 22 of the 42 patients (52%). Dissemination via cerebrospinal fluid (intraventricular or spinal) was present at the initial diagnosis in eight (36%) of the 22 cytology-positive patients and none of the 20 negative patients. After treatment, cerebrospinal fluid dissemination developed in four (18%) of the cytology-positive patients and one (5%) of the negative patients. Two of the former four patients had received chemotherapy alone as initial treatment. Five patients with positive cytology received irradiation to a smaller volume than the cerebrospinal axis (primary tumor site plus spinal axis in three and whole brain in two), but they have not developed recurrence in the 4 to 14 years since therapy. The 5-year survival rate was 93% for the cytology-positive patients and 94% for the negative patients. CONCLUSION: Cerebrospinal fluid cytology-positive patients have a higher risk of cerebrospinal fluid dissemination and it seems reasonable to give them low-dose (20-24 Gy) prophylactic craniospinal irradiation. When properly irradiated, the prognosis of cytology-positive patients is as good as that of negative patients.

Adolescent↗
PubMed1994

Fluorinated 2-nitroimidazole derivative hypoxic cell radiosensitizers: radiosensitizing activities and pharmacokinetics.

PURPOSE: To assess the effects of incorporation of a CF2 group into the side chain of a 2-nitroimidazole derivative, we evaluated the in vitro and in vivo radiosensitizing activities of KU-2285 (a 2-nitroimidazole derivative with an N1-substituent of -CH2CF2CONH(CH2)nOH, n = 2) and its related compounds in comparison with those of comparable nonfluorinated compounds. The pharmacokinetics of these compounds in murine tumors was also tested. METHODS AND MATERIALS: KU-2285, KU-3202 (n = 3) and KU-3207 (n = 4) are fluorinated 2-nitroimidazole derivative compounds with similar structures. Etanidazole (a 2-nitroimidazole derivative with an N1-substituent of -CH2CONH(CH2)nOH, n = 2) and its related compounds, KU-3205 (n = 3) and KU-3206 (n = 4) were also tested. The in vitro radiosensitizing activities of each compound for hypoxic cells was evaluated with a standard colony formation method. The in vivo radiosensitizing activities of these compounds were tested in female C3H/He mice bearing SCCVII tumors using an in vivo/in vitro clonogenic assay. The pharmacokinetic studies were performed in C3H/He mice bearing the SCCVII tumor. Samples were analyzed by reverse-phase high-performance liquid chromatography. RESULTS: The in vitro radiosensitizing activities of fluorinated 2-nitroimidazoles were higher than those of the nonfluorinated compounds. Although the in vivo radiosensitizing activity of KU-2285 was higher than that of etanidazole (p < 0.05), other fluorinated 2-nitroimidazoles showed less radiosensitizing activity than the comparable nonfluorinated compounds. The compound was eliminated from serum more rapidly with the increase in the number of CH2 group in the side chain of the compound in each series. CONCLUSION: Although the in vitro sensitizing activity of the fluorinated compounds was higher than that of the comparable nonfluorinated compounds, the in vivo radiosensitizing activity of all fluorinated compounds but KU-2285 was lower than that of comparable etanidazole group compounds, probably due to their lower molecular concentrations in tumor and rapid elimination.

Animals↗
PubMed1994

Reoxygenation in the SCCVII tumor after KU-2285 sensitization plus single or fractionated irradiation.

PURPOSE: Because reoxygenation of solid tumors after irradiation with a hypoxic cell sensitizer has never previously been investigated, we assessed the reoxygenation in SCCVII tumors after treatment with KU-2285 plus single or fractionated irradiation. METHODS AND MATERIALS: KU-2285 (100 mg/kg) was injected intraperitoneally into C3H mice bearing 1-cm SCCVII tumors at 30 min before a single dose of 12 Gy or three fractions of 5 Gy at 12 h intervals. Changes of the hypoxic fraction (HF) were then evaluated by the paired survival curve method. RESULTS: Since the radiosensitizing effect of KU-2285 was relatively persistent, the HF was only evaluable after 6 h of irradiation. The HF of untreated SCCVII tumors was 9.1%. After treatment with KU-2285 and 12 Gy, the HF was 25% at 6 h, 32% at 12 h, 24% at 24 h, and 7.6% at 72 h. The HF was lower at 6 h than that after radiation alone, but was similar at later periods. After three fractions of 5 Gy with or without KU-2285, the HF was 33% at 6 h in both groups, while it was 12% and 13% at 24 h for tumors pretreated with KU-2285 and those receiving radiation alone, respectively. However, a sensitizing effect of KU-2285 was indicated by the downward shift of the survival curves for tumors irradiated after exposure to this agent. CONCLUSION: Reoxygenation occurred quite efficiently in tumors receiving KU-2285 and 12 Gy. After fractionated irradiation, however, reoxygenation was similar in the KU-2285-pretreatment and irradiation alone groups.

Animals↗
PubMed1994

Comparison of radiosensitizing effect of KU-2285 and SR-2508 at low drug concentrations and doses.

PURPOSE: Since the radiosensitizing effect of KU-2285 at relatively low dose levels is not known, we investigated its efficacy at such low concentrations or doses achievable in humans with oral administration of 0.3-1.0 g/m2. METHODS AND MATERIALS: KU-2285 was tested in comparison with SR-2508 at low concentrations (0.05-0.25 mM) in vitro by the cytokinesis-block micronucleus assay and by the colony formation assay, and at low drug doses (12.5-50 mg/kg) in vivo by the in vivo-in vitro assay and by the growth delay assay using SCC VII tumors in C3H/He mice. RESULTS: In the cytokinesis-block micronucleus assay, the sensitizer enhancement ratio (SER) for KU-2285 and SR-2508 was 1.43 and 1.17 at 0.05 mM, 1.75 and 1.27 at 0.10 mM, and 2.14 and 1.69 at 0.25 mM, respectively. In the colony formation assay, the SER for KU-2285 was also greater than that for SR-2508. In the in vivo-in vitro assay, the SER for KU-2285 and SR-2508 was 1.11 and 1.04 at 12.5 mg/kg, 1.21 and 1.04 at 25 mg/kg, and 1.26 and 1.18 at 50 mg/kg, respectively. In the growth delay assay at 50 mg/kg, no tumor regrowth was observed in four of the 18 mice treated with KU-2285 + 25 Gy, although the growth delay time for the remaining mice was similar to that for SR-2508 + 25 Gy. CONCLUSION: KU-2285 was more effective than SR-2508 both at low drug concentrations in vitro and at low drug doses in vivo. These promising findings suggest the potential superiority of KU-2285 over SR-2508 as a radiosensitizer for clinical use.

Animals↗
PubMed1994

Radiosensitizing activity and pharmacokinetics of multiple dose administered KU-2285 in peripheral nerve tissue in mice.

PURPOSE: In a clinical trial in which a 2-nitroimidazole radiosensitizer was administered repeatedly, the dose-limiting toxicity was found to be peripheral neuropathy. In the present study, the in vivo radiosensitizing activity of KU-2285 in combination with radiation dose fractionation, and the pharmacokinetics of cumulative dosing of KU-2285 in the peripheral nerves were examined. METHODS AND MATERIALS: The ability of three nitroimidazoles, misonidazole (MISO), etanidazole (SR-2508) and KU-2285, to sensitize SCCVII tumors to radiation treatment has been compared for drug doses in the range 0-200 mg/kg. Single radiation doses or two different fractionation schedules (6 Gy/fractions x three fractions/48 h or 5 Gy/fractions x five fractions/48 h) were used; the tumor cell survival was determined using an in vivo/in vitro colony assay. The pharmacokinetics in the sciatic nerves were undertaken, when KU-2285 or etanidazole were injected at a dose of 200 mg/kg intravenously one, two, three or four times at 2-h intervals. RESULTS: At less than 100 mg/kg, KU-2285 sensitized SCCVII tumors more than MISO and SR-2508 by fractionated irradiation. Evaluation of pharmacokinetics in the peripheral nerves showed that the apparent biological half-life of SR-2508 increased with the increases in the number of administrations, whereas that of KU-2285 became shorter. CONCLUSION: Since most clinical radiotherapy is given in small multiple fractions, KU-2285 appears to be a hypoxic cell radiosensitizer that could be useful in such regimens, and that poses no risk of chronic peripheral neurotoxicity.

Animals↗
PubMed1994

KIN-804 vs. KU-2285 as a radiosensitizer for clinical use.

PURPOSE: The in vitro and in vivo effects of two promising hypoxic cell radiosensitizers, KIN-804 (KIN) and KU-2285 (KU), were compared using four types of assays, and the acute toxicity and pharmacokinetics of KIN were investigated to evaluate the clinical applicability of the compounds. METHODS AND MATERIALS: To evaluate the in vitro effect at low radiation doses (1-4.5 Gy), the cytokinesis-block micronucleus (MN) assay using SCCVII or EMT-6 cells and the chromosomal aberration (CA) assay using EMT-6 cells were performed. In addition, an in vivo-in vitro colony assay, a growth delay assay, and a pharmacokinetic study were performed using C3H mice bearing SCCVII tumors, and the LD50/7 was determined in ICR mice. RESULTS: In the in vitro MN assay, the sensitizer enhancement ratio (SER) at 0.1, 0.25, 1, and 5 mM with SCCVII cells, and at 1 mM with EMT-6 cells was respectively, 1.45, 1.61, 2.57, 4.22, and 1.96 for KIN, and 1.57, 1.62, 2.59, 5.66, and 2.21 for KU. In the in vitro CA assay, the SER at 1 mM was 1.78 for KIN and 1.79 for KU. In the in vivo-in vitro colony assay, the SER of KIN at 50, 100, and 200 mg/kg was 1.24, 1.30, and 1.45, respectively, while the SER of KU at 100 mg/kg was 1.41. In the growth delay assay, the growth delay time for 100 and 200 mg/kg of the drug plus 20 Gy of radiation was respectively, 16.5 and 19.1 days for KIN, and 18.9 and 24.0 days for KU. In all experiments, the sensitizing effect of KIN was almost equal to that of KU. The LD50/7 of KIN was 3.6 g/kg by intraperitoneal injection, while that of KU was 3.6 g/kg by intraperitoneal injection, and the pharmacokinetic study of KIN revealed a low uptake of the drug by the brain. CONCLUSION: Both KIN and KU had a definite sensitizing effect even at lower drug concentrations or doses, suggesting their potential usefulness in clinical radiotherapy.

Animals↗
PubMed1994

Influence of extent of surgery and tumor location on treatment outcome of patients with glioblastoma multiforme treated with combined modality approach.

Between 1988 and 1991, eighty-six patients with glioblastoma multiforme were evaluated in order to define the influence of extent of surgery and tumor location on treatment outcome. Patients underwent surgery followed by postoperative hyperfractionated radiotherapy and chemotherapy delivered according to one of two consecutive protocols. Surgery consisted of biopsy in 25 (29%) patients and subtotal or gross total tumor resection in 61 (71%) patients. Frontally located tumors were noted in 26 (30%) patients and other tumor locations were noted in 60 (70%) patients. Patients having more radical surgery had longer median survival time (MST) and higher 1- and 2-year survival rates than those with biopsy only (56 vs 29 weeks, respectively; 62% and 23% vs 16% and 0%, respectively; p = 0.00000). Patients having frontally located tumors had longer MST and higher 1- and 2-year survival rates than those with other tumor locations (101 vs 47 weeks, respectively; 76% and 44% vs 37% and 2.5%, respectively; p = 0.00001). Multivariate analysis confirmed that extent of surgery and tumor location were independent prognostic factors in patients with glioblastoma multiforme. Regarding progression-free survival, patients having more radical surgery had longer median time to tumor progression (MTP) than those with biopsy only (33 weeks vs 21 weeks, respectively). Also, progression-free survival at 1 year was higher in radically resected group than in biopsy only group (20% vs 0%, respectively; p = 0.00000). Patients with frontally located tumors had longer MTP (42 weeks) and higher progression-free survival at 1 year (42%) than those with other tumor location (28 weeks and 1.7%, respectively; p = 0.00002).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗