A phase I trial of tocoferol monoglucoside in patients undergoing hemi-body radiation.

PURPOSE: To evaluate Tocoferol monoglucoside (TMG), a water soluble vit. E. in a phase I trial, as a radiation protector in those undergoing hemi-body radiation for disseminated disease. MATERIALS AND METHODS: Patients scheduled to receive modified hemi-body radiation were accrued for the study. Patients not only had disseminated skeletal disease but, were heavily pretreated Seven patients were accrued for the study. Patients received 1 and 2 gms of TMG. 30-40 minutes before hemibody radiation. A dose of 600 cGy was delivered on telecobalt equipment at mid plane. Immediate Toxicities were evaluated as well as response to pain. RESULTS: All the seven patients underwent radiation uneventfully. There was no drug related toxicity. Pain relief was adequate. CONCLUSION: Tocoferol monoglucoside an effective antioxidant with no significant acute toxicity, when administered in a dose of 1 or 2 gms per oral route. TMG being water-soluble can have global antioxidant and radio protective effects. This needs further clinical evaluation.

Preparation and preliminary biological evaluation of a 177Lu labeled sanazole derivative for possible use in targeting tumor hypoxia.

The preparation of a polyazamacrocyclic-nitrotriazole conjugate for radiolabeling with the therapeutic radioisotope viz. (177)Lu is described. The nitroimidazole used for the present study is [N-2'(carboxyethyl)-2-(3'-nitro-1'-triazolyl)acetamide], the carboxylic acid derivative of sanazole, which possesses an optimal combination of desired properties such as, selective toxicity for hypoxic cells, lowered lipophilicity resulting in lowered neurotoxicity. The bifunctional chelating agent is a DOTA derivative viz. 1,4,7,10-tetraaza-1-(4'-aminobenzylacetamido)-cyclododecane-4,7,10- triacetic acid (p-amino-DOTA-anilide). (177)Lu was produced in adequate specific activity (110TBq/g) and high radionuclidic purity (approximately 100%) by irradiating enriched (60.6% (176)Lu) Lu(2)O(3) target and used for radiolabeling of the sanazole-BFCA conjugate. approximately 98% Complexation yield was achieved under optimized conditions. The complex has been characterized by paper chromatography and HPLC studies. Bioevaluation studies in Swiss mice bearing fibrosarcoma tumors revealed moderate tumor uptake (0.88%/g at 1h post-injection) with favorable tumor to blood (4.00 at 1h post-injection) and tumor to muscle (4.63 at 1h post-injection) ratios.

In vivo postirradiation protection by a vitamin E analog, alpha-TMG.

The water-soluble vitamin E derivative alpha-TMG is an excellent radical scavenger. A dose of 600 mg/kg TMG significantly reduced radiation clastogenicity in mouse bone marrow when administered after irradiation. The present study was aimed at investigating the radioprotective effect of postirradiation treatment with alpha-TMG against a range of whole-body lethal (8.5-12 Gy) and sublethal (1-5 Gy) doses of radiation in adult Swiss albino mice. Protection against lethal irradiation was evaluated from 30-day mouse survival and against sublethal doses was assessed from micronuclei and chromosomal aberrations in the bone marrow 24 h after irradiation. An intraperitoneal injection of 600 mg/kg TMG within 10 min of lethal irradiation increased survival, giving a dose modification factor (DMF) of 1.09. TMG at doses of 400 mg/kg and 600 mg/kg significantly reduced the percentage of aberrant metaphases, the different types of aberrations, and the number of micronucleated erythrocytes. DMFs of 1.22 and 1.48 for percentage aberrant metaphases and 1.6 and 1.98 for micronuclei were obtained for 400 mg/kg and 600 mg/kg TMG, respectively. No drug toxicity was observed at these doses. The effectiveness of TMG when administered postirradiation suggests its possible utility for protection against unplanned radiation exposures.

Sanazole as a sensitizer of hypoxic cells with radical radiation in the treatment of advanced cancer of cervix an Indian experience.

AK-2123, is a nitrotriazole with a potential to sensitize hypoxic tissue to radiation. Cancer of cervix in advanced stages are predominantly treated with radiation. These are the tumours which harbour a large hypoxic core. This is an Indian experience of the multicentric trial. Patients were randomized to control and AK-2123 arm. 49 patients were randomized to each group. Patients received external radiation with telecobalt to a dose of 50 Gy in five weeks. Those in the study arm received 600 mg/m2, on alternate days. The patients were further treated with intracavitory radiation a dose of 20 Gy. The total dose of 70 Gy was achieved. Patients in the study arm had a complete response of 71.43% (35 of 49) while only 21 of 49 (42.86%) responded in the control group. The overall survival at two years was 72.2% for the study group and 32.43% for control. Neuropathy, a drug related toxicity was transient except, in one patient, which has persisted. AK-2123, has shown significant radiation sensitizing potential.

Sanazole as substrate of xanthine oxidase and microsomal NADPH/cytochrome P450 reductase.

The influence of sanazole and metronidazole on cytochrome C (Cyt c(3+)) reduction in the enzyme systems xanthine/xanthine oxidase and NADPH-cytochrome P450 reductase was studied. The addition of sanazole but not metronidazole significantly increased the rate of Cyt c(3+) reduction in both enzyme systems. The Lineweaver-Burk plot of the rate of Cyt c(3+) reduction (in xanthine/xanthine oxidase system) versus sanazole concentration indicates that the apparent K(m) for sanazole is about 1.5 mM (in hypoxic medium). The results obtained suggest that xanthine oxidase and microsomal NADPH/cytochrome P450 reductase can be enzymes participating in sanazole bioactivation and manifestation of its radiosensitizing and tumoricidal activity. It is concluded that the ability of sanazole to selectively bioactivate in hypoxic tumor tissue and form immunogenic conjugates with tumor protein can be a starting-point for developing nitroazole drugs with immunomodulation anticancer properties.

In vivo radioprotection by alpha-TMG: preliminary studies.

alpha-TMG is a novel water-soluble derivative of Vitamin E that has shown excellent antioxidant activity. The parent compound has demonstrated protection against radiation induced chromosomal damage in vivo. Hence, the preliminary experiments to determine the radioprotective activity of alpha-TMG were carried out in adult Swiss albino mice. Acute toxicity of the drug was studied taking 24h, 72 h and 30 day mortality after a single intraperitoneal injection of 500-2000 mg/kg body weight of the drug. The drug LD(50) for 24h and 72 h/30 day survival were found to be 1120 and 1000 mg/kg body weight, respectively. The optimum time of drug administration and drug dose-dependent effect on in vivo radiation protection of bone marrow chromosomes was studied in mice. Injection of 600 mg/kg of the drug 15 min before or within 5, 15 or 30min after 3Gy whole body gamma radiation resulted in a significant decrease in the aberrant metaphases percent at 24h post-irradiation; the maximum effect was seen when the drug was given immediately after irradiation. Injection of 200-800 mg/kg TMG within 5 min of irradiation with 3 Gy produced a significant dose-dependent reduction in the radiation induced percent aberrant metaphases and in the frequency of micronucleated erythrocytes at 24h after exposure, with a corresponding decrease in the different types of aberrations. The optimum dose for protection without drug toxicity was 600 mg/kg body weight. At this dose, TMG produced 70 and >60% reduction in the radiation induced percent aberrant metaphases and micronucleated erythrocytes, respectively. The high water solubility and effectiveness when administered post-irradiation favor TMG as a likely candidate for protection in case of accidental exposures.

Effect of a water soluble derivative of alpha-tocopherol on radiation response of Saccharomyces cerevisiae.

The radioprotection conferred by a highly water soluble glucose derivative of alpha-tocopherol, namely, 2-(alpha-D-glucopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol (TMG) in Saccharomyces cerevisiae was studied. Cells grown in standard YEPD-agar medium and irradiated in the presence of TMG showed a concentration dependent higher survival up to 10 mM of TMG in comparison to cells irradiated in distilled water. Treatment of TMG to cells given either before or immediately after irradiation but not during irradiation, had no effect on their radiation response. S. cerevisiae strain LP1383 (rad52) which is defective in recombination repair showed enhanced radioresistance only when subjected to irradiation in presence of TMG. Cells of rad52 strain grown in the medium containing TMG showed a radiation response similar to that of cells grown in the medium without TMG. The nature of TMG dependent enhanced radioresistance was studied by scoring the mutations in the strain D-7, which behaved like wild type strain in complete medium, at trp and ilv loci. Our study indicated that TMG confers radioresistance in S. cerevisiae possibly by two mechanisms viz. (i), by eliminating radiation induced reactive free radicals when the irradiation is carried out in the presence of TMG and (ii), by activating an error prone repair process involving RAD52 gene, when the cells are grown in the medium containing TMG.

The use of a hypoxic cell radiosensitizer AK-2123 gave no improvement in thermoradiotherapy combined with hydralazine.

An electron-affinic compound, AK-2123, and the anti-hypertensive agent, hydralazine, were combined with radiation and hyperthermia for treatment of murine SCC-VII tumours. Hydralazine markedly decreased tumour perfusion while AK-2123 had no influence on it. Hydralazine enhanced the tumouricidal effects of hyperthermia alone and in combination with radiation. AK-2123 provided a radiosensitization which was significant only in tumours irradiated without supplementary hyperthermia. The greatest tumour response was achieved when thermoradiotherapy was combined with hydralazine alone; the additional use of AK-2123 with this treatment combination did not further increase the effect. It is concluded that hydralazine plus heat virtually eliminated a hypoxia-related radioresistance in tumours, thus removing the requirement for AK-2123 administration.

Intratumoral and parametrial infusion of a 3-nitrotriazole (AK-2123) in the radiotherapy of the uterine cervix cancer: stage II-III--preliminary positive results.

Based on a clinical differential effect of the action of a new hypoxic cell radiosensitizer, AK-2123 (a 3-nitro-1,2,4-triazole), on locally advanced cervix cancer (Stage II-B and III-B), a Phase I/II clinical trial has been carried out on 80 consecutive patients. They were intratumorally injected with AK-2123, wt 1% and 2%, 30 min before the delivery of external radiation therapy. The short-term effects show that exophytic types of lesions respond far better than endophytic types and AK-2123 may be replacing intracavitary radium for exophytic Stage II-B cervix cancer as the standard therapy for this neoplasm in our patients. Treatment is well tolerated and no neurological toxicity has been noted.

Metabolic rate modification of nitrotriazole radiosensitizers by sulfur substitution of side chain.

The pharmacokinetic properties and radiosensitizing activities in vitro and in vivo of a series of 3-nitro-1,2,4-triazole (NTA) derivatives with a -CH2(C = Y)NH(CH2)nZCH3 (Y, Z = O or S; n = 2 or 3) group in the side chain at N-1 position of NTA were investigated with respect, particularly, to the effects of sulfur substitution in the side chain of NTA. The sulfur substitution for an oxygen atom in the side chain NTA radiosensitizers increased the rho value, but gave rise to little effect on the one-electron reduction potential. The derivatives bearing a thioether group (-CH2SCH3) in the side chain were slightly less effective both in vitro on hypoxic EMT6/KU cells and in vivo on SCCVII tumors than their oxygen analogs (-CH2OCH3). The thioether compounds tended to metabolize rapidly. The thioamide compound showed high sensitizing activity in vitro, but metabolized very slow.

Fluorine modification of nitroazole radiosensitizers for the enhancement of sensitizing activity with lowering toxicity: a pharmacokinetic characterization.

Pharmacokinetic characterization of various nitroazole radiosensitizers was carried out to clarify the effect of fluorine modification of the side-chain groups on the sensitizing activity and the acute toxicity. The in vivo tumor/plasma partition coefficient (PTP) of sensitizers increased with increase in the octanol/water partition coefficient (Pow) up to approximately 0.3 and was almost unity (maximum) for sensitizers with their Pow values larger than approximately 0.3. This relationship was observed commonly for all types of sensitizers independent of the fluorine modification. The in vivo brain/plasma partition coefficient (PBP) of sensitizers increased with increase in the Pow, attaining a constant value of almost unity at Pow greater than 0.5 for non-fluorine sensitizers or at Pow greater than 1.5 for fluorine-modified sensitizers. The maximum brain-affinity factor ((FB,t)max = (CB,t)max/Ds, where (CB,t)max and Ds are the maximum intrabrain concentration and the administered dose of sensitizer, respectively) was proportional to the maximum tumor-affinity factor ((FT,t)max = (CT,t)max/Ds, where (CT,t)max is the maximum intratumor concentration of sensitizer), depending on the side-chain structure of the sensitizer. A series of non-fluorine and fluorine-modified nitroazole derivatives, including N-(2'-hydroxyethyl)-2,2-difluoro-3-(3''-nitro-1'-triazolyl)propionamide (KU-2285), gave a smaller brain to tumor ratio of approximately 1/7. The toxicity index defined by 1/LD50/7 was parallel to the sensitizing activity measured by 1/DS,1.5 (DS,1.5 is the sensitizer dose to obtain the SER of 1.5 in vivo). The therapeutic risk index defined by Ds,1.5/LD50/7 depended on the side-chain structures of sensitizers. The DB,1-5LD50-/7 values of KU-2285 and ethanidazole (SR-2508) were 1/3 that of misonidazole (MISO). The sensitizers were smaller Ds,1.5/LD50/7 values showed higher sensitizing activities as their tumor affinities increased, without an increase in serious toxicity.