Hypoxic Cell Radiosensitizer Misonidazole Research Articles

The effect of radiosensitizers on radio‐immunotherapy, using 131I‐Labelled anti‐cea antibodies in a human colonic xenograft model

Anti-CEA antibodies were used for radio-immunotherapy in an established LS174T colonic xenograft in nude mice. A single IV dose of either 131I-PK4S (polyclonal) or -A5B7 (monoclonal) antibody produced tumour regression, and significantly delayed subsequent tumour growth. Administration of a clearing second antibody, 24 hr post 131I-PK4S and at 5 times the dose, significantly reduced the therapeutic effect of radio-antibody alone. Tumours of mice given non-specific antibody or unlabelled anti-CEA antibody grew like those of untreated controls. In an attempt to enhance therapy without increasing dose, radiosensitizers normally employed with external beam radiation were used in combination therapy. When the hypoxic cell radiosensitizer misonidazole was combined with 131I-A5B7, it significantly prolonged tumour-growth inhibition over radio-antibody alone. Conversely, the therapeutic effect of either radio-antibody was significantly reduced when used in combination with the halogenated pyrimidine radiosensitizer 5-iododeoxyuridine. Neither sensitizer alone affected tumour growth.

Tumor bed effect-induced reduction of tumor radiocurability through the increase in hypoxic cell fraction

Two murine tumors, designated FSA and SA-NH, that exhibit strong tumor bed effect (TBE), were found to be less radiocurable if they grew in the preirradiated s.c. tissue. Tumors were transplanted into the right thighs irradiated with 30 Gy one day earlier, and were irradiated when they grew to 6 mm. The TBE-caused reduction in tumor radiocurability was manifested by the increase in TCD50 values. Tumor irradiation under hypoxic conditions increased TCD50 values less, and the hypoxic cell radiosensitizer misonidazole reduced TCD50 values more, when tumors grew in preirradiated than when they grew in unirradiated legs. This implies that TBE-induced increase in TCD50 was due to increase in hypoxic fraction of tumor cells. For 6 mm SA-NH tumor the estimated increase in hypoxic cell fraction was from the control value of 3% to 12%. Thus, TBE causes the reduction in tumor radiocurability through the increase in hypoxic fraction of tumor cells.

Effect of the radiosensitizer misonidazole and the radioprotector diethyldithiocarbamate on spontaneous metastasis formation of murine tumors

The effect of treatment with the hypoxic cell radiosensitizer misonidazole (MISO) and the radioprotector diethyldithiocarbamate (DDC) on the formation of spontaneous lung metastases of four different spontaneously metastasizing murine tumors was investigated. The tumors were mammary carcinoma MCA-K, hepatocarcinoma HCA-1, and sarcomas SA-4020 and SA-NH. Multiple daily treatments with MISO significantly enhanced the incidence of metastases only in MCA-K. Because only MCA-K, but not the three remaining tumors, is immunogenic, the treatment with MISO may be associated with the promotion of metastasis primarily in the immunogenic tumors. Treatment of mice with DDC had no influence on metastatic spread. However, when given prior to 1,3-bis(2chloroethyl)-1-nitrosourea (BCNU), DDC reduced BCNU-induced enhancement of HCA-1 metastases.

Renal elimination of the hypoxic cell radiosensitizer misonidazole in Wistar rats: influence of some drugs on its excretion.

The hypoxic cell radiosensitizing drug, misonidazole (Miso) (Ro 07-0582) and its demethylated metabolite were administered to Wistar rats at different dose levels to examine their renal elimination. The data were consistent with a model in which Miso is eliminated mainly after biotransformation into desmethylmisonidazole (Demiso) which is eliminated according to its renal clearance. The study of Miso renal elimination process shows a tubular reabsorption. So we analyzed the interaction of various drugs on urinary 24 hours elimination of this radiosensitizer. Following results were observed: Furosemide and acetazolamide do not change the rate of renal elimination of the drug; Soludactone increases the elimination level of unmetabolized Miso (p less than 0.01); Under probenecid treatment, the elimination of Miso and its O-demethylated derivative are increased; On the other hand, after a pretreatment with phenobarbital, the urinary level of desmethylmisonidazole is strongly increased (p less than 0.001).

Enhancement of artificial lung metastases by misonidazole

The effect of treatment with the hypoxic cell radiosensitizer misonidazole on the formation of artificial lung metastases was examined. Both single treatments with large doses of misonidazole and fractionated treatments with smaller doses of misonidazole were found to increase the number of lung tumors developing after intravenous injection of EMT6 mouse mammary carcinoma cells. The immunologic and physiologic effects of the nitroimidazole were postulated to be responsible for the enhancement of lung tumor formation.

Response of an experimental mammary carcinoma to fractionated X-irradiation with misonidazole and microwave hyperthermia

X/Gf mice bearing the MT2 mammary adenocarcinoma were subjected to 4,000 rad of X rays given either as a single dose, or five daily fractions of 800 rad. Additional experimental groups were treated with either short term localized microwave hyperthermia (LMH) (42.5°C for 25 min.), or the hypoxic cell radiosensitizer misonidazole (MISO) (0.67 mg/g bw), or both hyperthermia plus MISO with X rays. The combined use of MISO plus 42.5°C with X rays was superior to the other treatment regimens as assessed by tumor regrowth delay and mean survival time. However, for the five fraction schedule, the addition of MISO plus hyperthermia was not as effective as observed for the single dose treatment. This may be attributed to reoxygenation of the hypoxic tumor cells between treatment fractions. MISO retention in tumor tissue under ambient and hyperthermic conditions was studied. The application of heat locally to the tumors caused a significant increase in MISO tumor concentration. However, after four X ray fractions the influence on MISO concentration by hyperthermia in the tumors could not be demonstrated. This may be related to the stromal damage by X rays in the tumor. tissue that was observed histologically.

Systemic, bladder wall, and bladder tumor concentration of isonidazole following intravesical administration in the rat

The hypoxic-cell radiosensitizer misonidazole was administered intravesically to normal and to bladder tumor-bearing female Fischer rats. Drug concentration was measured in the bladder wall, the tumor and in the serum using high pressure liquid chromatography at different times following administration. The data show that misonidazole is readily absorbed by the bladder wall and the tumor with tissue levels reaching up to 10 times those measured in the serum.

No significant effect of metoclopramide on misonidazole elimination in man.

British Journal of Clinical PharmacologyVolume 15, Issue 3 p. 390-392 Free Access No significant effect of metoclopramide on misonidazole elimination in man. KM Williams, KM WilliamsSearch for more papers by this authorEJ Begg, EJ BeggSearch for more papers by this authorDN Wade, DN WadeSearch for more papers by this authorK O'Shea, K O'SheaSearch for more papers by this author KM Williams, KM WilliamsSearch for more papers by this authorEJ Begg, EJ BeggSearch for more papers by this authorDN Wade, DN WadeSearch for more papers by this authorK O'Shea, K O'SheaSearch for more papers by this author First published: March 1983 https://doi.org/10.1111/j.1365-2125.1983.tb01519.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References DISCHE, S., SAUNDERS, M.I., LEE, M.E., ADAMS, G.W. & FLOCKHART, I.R. (1977). Clinical testing of the radiosensitizer Ro 07–0582: experience with multiple doses. Br. J. Cancer, 35, 567– 579. SAUNDERS, M.I., DISCHE, S., ANDERSON, P. & FLOCKHART, I.R: (1978). The neurotoxicity of misonidazole and its relationship to dose, half-life and concentration in the serum. Br. J. Cancer, 37, 268– 270. WILLIAMS, K.M., BEGG, E.J., WADE, D.N. & O'SHEA, K. (1983). The effects of phenytoin, phenobarbitone and ascorbic acid on the elimination of misonidazole in man. Clin. Pharmac. Ther., (in press). WORKMAN, P. (1979). Effects of pretreatment with phenobarbitone and phenytoin on the pharmacokinetics and toxicity of misonidazole in mice. Br. J. Cancer, 40, 335– 353. WORKMAN, P., BLEEHEN, N.M. & WILTSHIRE, C.R. (1980). Phenytoin shortens the half-life of the hypoxic cell radiosensitizer misonidazole in man: implications for possible reduced toxicity. Br. J. Cancer, 41, 302– 304. Volume15, Issue3March 1983Pages 390-392 ReferencesRelatedInformation

Combined Effects of Misonidazole Radiosensitization and Hypoxic Cell Toxicity in Mammalian Cells

It has been established that the hypoxic cell radiosensitizer misonidazole (Ro-07-0582) is also a toxic agent to hyposic cells in the absence of radiation. In this study, the combined effects of radiation sensitization and toxicity were examined in hypoxic CHO cells. Complete radiation survival curves were measured for cells in the presence of 15 mM misonidazole prior to or following incubation with the drug for various times in hypoxia at 37/sup 0/C. The latter case is the condition for the preincubation effect observed previously for misonidazole. The cells were irradiated as a monolayer in stoppered glass flasks with 280-kVp x rays; survival was assayed by colony formation. The survival data obtained in these experiments were analyzed by comparing the experimentally observed survival curves with those theoretically predicted based on the concepts of independent and additive interaction of the two effects of hypoxic cell toxicity and radiation sensitization. For incubation times of 1 to 3 hr, for which the cytotoxic effect is moderate, the combined response appears to be of an additive rather than an independent nature. The data in fact suggest a somewhat greater than additive response, and also a slight change in the slope as well as the shouldermore » of the survival curve, when compared with the predicted curves. The results are discussed with regard to both in vitro and in vivo studies.« less

Misonidazole and radiotherapy to treat malignant glioma: a phase II trial of the radiation therapy oncology group.

Abstract Fifty-four patients with Grade III or IV malignant glioma were treated with the hypoxic-cell radiosensitizer misonidazole, and radiation therapy (RT) in a Phase II trial of the Radiation Therapy Oncology Group (RTOG). The median survival was 39 weeks. Toxicity was acceptable. Almost all toxicities were reversible and self-limited. The were no significant changes in hematologic, hepatic or renal parameters. The median survival obtained is similar to the results with conventional radiotberapy. A Phase III trial is under way comparing standard radiation and BCNU chemotherapy (1,3-bis (2-chloroethyl)-1-nitrosourea) with sensitized radiation and chemotherapy (RT + misonidazole + BCNU). Additive toxicity between misonidazole and BCNU was not observed in a pilot group.

Radiosensitization by misonidazole of a human malignant melanoma grown in athymic nude mice.

Abstract A human malignant melanoma grown in the athymic mutant nude mouse has been subjected to acute and fractionated irradiation in the presence and absence of the hypoxic-cell radiosensitizer misonidazole (Ro-07–0582). A 60Co therapy unit was used for local irradiation of nonanaesthetized mice. Misonidazole in doses of 500 mg/kg bodyweight was administered to the mice by intraperitoneal injection 45 minutes before each exposure. In the first series of experiments the enhancement ratio of misonidazole was determined for fractionation regimes with constant interfraction time (one day) and varying number of fractions. For a single dose of 12.50 Gy, three fractions of 4.52 Gy in three days, four fractions of 3.75 Gy in four days and ten fractions of 2.07 Gy in ten days, the enhancement ratio was found to be 1.4–1.5, 1.15, 1.05 and 1.0 respectively. In the second series of experiments the enhancement ratio was determined for fractionation regimes with a constant number of fractions (three) and varying inte...

Phenytoin shortens the half-life of the hypoxic cell radiosensitizer misonidazole in man: implications for possible reduced toxicity.

Phenytoin shortens the half-life of the hypoxic cell radiosensitizer misonidazole in man: implications for possible reduced toxicity

Effects of pretreatment with phenobarbitone and phenytoin on the pharmacokinetics and toxicity of phenytoin on the pharmacokinetics and toxicity of misonidazole in mice.

Concentrations of the hypoxic cell radiosensitizer misonidazole (MIS) and its O-demethylated metabolite Ro 05-9963 were determined in plasma (or blood), brain and tumour after injection of 1 g/kg MIS i.p. to control mice or mice pretreated with 4-6 daily injections of phenobarbitone or phenytoin. Analysis was by high-performance liquid chromatography (HPLC). Phenobarbitone and phenytoin did not alter the peak MIS concentration in plasma, brain or tumor. However, the apparent elimination half-life (t 1/2) for MIS was reduced by 20-67%, and the area under the curve (AUC) was decreased by 23-49% in plasma, brain and tumour. The decrease in MIS t 1/2 was associated with an initially increased Ro 05-9963 metabolite concentration. However, the AUC for total 2-nitromidazole (MIS + Ro 05-9963) in plasma, tumour and brain was reduced by 20-50%. Urinary excretion of MIS and its metabolites accounted for 15-42% of the injected dose, and was unaltered by pretreatment with phenobarbitone or phenytoin. Tumour/plasm and brain/plasma concentration ratios for MIS, and tumour/plasma ratios for Ro 05-9963 were very similar, but the brain/tumour ratios for Ro 05-9963 were considerably lower. Tissue/plasma ratios were unaltered by pretreatment with phenobarbitone or phenytoin. The acute LD50 for MIS was increased from 1.54 to 1.90 g/kg after phenobarbitone pretreatment and 1.78 g/kg after phenytoin pretreatment. In addition, pretreatment with either compound shortened the duration of the MIS-induced decrease in body temperature. These data suggest that pretreatment with microsomal-enzyme-inducing agents may reduce the toxicity of MIS without affecting the radiosensitization. The significance of these findings for the mechanism of MIS toxicity is also discussed.

Radiosensitizing effect of misonidazole in fractionated gamma-ray treatment of a human malignant melanoma grown in athymic nude mice

The effect of the hypoxic cell radiosensitizer misonidazole (Ro-07-0582) has been tested on a human malignant melanoma grown subcutaneously in the athymic mutant nude mouse. A 60Co therapy unit was used for local irradiation of the animals. The tumours were exposed daily to 3.75 Gy (375 rad) over four consecutive days, to a total dose of 15.0 Gy. Misonidazole in doses of 500 mg/kg bodyweight was administered intraperitoneally in the mice 45 minutes before each irradiation. The time necessary for the tumours to regrow to their original sizes was compared with that of tumours treated with four daily fractions of 3.75, 4.50 and 5.25 Gy without sensitizer. The enhancement ratio of misonidazole was found to be 1.05.

Pharmacokinetic and Metabolic Studies of the Hypoxic Cell Radiosensitizer Misonidazole

1. The metabolism of the radiosensitizing 2-nitroimidazole, misonidazole, has been investigated in mice, rats, baboons, human volunteers, and in patients receiving radiotherapy for advanced malignant disease. 2. Plasma levels of unchanged drug and its desmethylated metabolite have been measured, and in humans there is good correlation of peak plasma concn. with drug dose. All drug-related material in plasma was accounted for as unchanged misonidazole or its desmethylated metabolite, both compounds being radiosensitizers in vitro. 3. Extensive faecal excretion of material not containing any nitro group occurred in mice, rats, and baboons dosed with radiolabelled drug. 4. Renal excretion is the preferred route of elimination in man, baboon and mouse. Nitroimidazole metabolites accounting for over half the urinary excretion in all species were identified. 5. The compound penetrates solid murine tumours in concentrations sufficient to achieve radiosensitization.