Biomedical subjects

D J Grdina

Publications and source records attributed to D J Grdina.

At least 37 records · Page 2Linked to original sources

PubMed1994

Oxymetry deep in tissues with low-frequency electron paramagnetic resonance.

We have measured the oxygen concentration in the body water of murine FSa and NFSa fibrosarcomas using a new method for quantitative oxygen concentration determination deep in the tissues of a living animal. The measurement uses unusually low-frequency electron paramagnetic spectroscopy sensitive to substrate 7 cm deep in tissue, partially deuterated spin probes (spin labels of molecular mass 195, approximating that of glucose) whose distribution compartment can be targeted with facile adduct substitution, and novel analytic techniques. We show that the water-compartment oxygen concentration of the tumors decreases as the tumor size increases and also shows a trend to decrease as radiobiologic hypoxia increases. An oxymetric spectral image of the tumor is presented. The technique will improve with larger human tissue samples. It provides the potential to quantitatively assess tissue hypoxia in ischemic or preischemic states in stroke and myocardial infarction. It will allow direct assessment of tumor hypoxia to determine the usefulness of radiation and chemotherapy adjuvants directed to hypoxic cell compartments.

Animals↗

PubMed1994

Radioprotection by WR-151327 against the late normal tissue damage in mouse hind legs from gamma ray radiation.

PURPOSE: To evaluate the protective effect of WR-151327 on late radiation-induced damage to normal tissues in mice. METHODS AND MATERIALS: The right hind legs of mice with or without WR-151327 administration (400 mg/kg) were irradiated with 137Cs gamma rays. Leg contracture and skin shrinkage assays were performed at 380 days after irradiation. The mice were killed on day 400 postirradiation and histological sections of the legs were made. The thickness of the dermis, epidermis, and skin (dermis plus epidermis) was measured. The muscular area of the legs and the posterior knee angle between the femur and tibia were also measured. The left hind legs were similarly assessed as nonirradiated controls. Group means and standard deviations were calculated and dose-response curves were drawn for every endpoint. Then, the dose modifying factor (DMF) for each endpoint and the correlations among endpoints were determined. RESULTS: Late damage assayed by leg contracture and skin shrinkage progressed with increasing radiation dose. However, it was reduced by drug treatment. The significant effect was indicated for skin shrinkage by a DMF of 1.8 at 35%. The DMF for leg contracture was 1.3 at 6 mm. In the irradiated legs, epidermal hyperplasia and dermal fibrosis in the skin, muscular atrophy, and extension disturbance of the knee joint were observed. These changes progressed with increasing radiation dose. Skin damage assayed by the present endpoints was also reduced by drug treatment by DMFs of 1.4 to 1.7. However, DMFs for damage to the muscle and knee were not determined because no isoeffect was observed. There were good correlations between leg contracture or skin shrinkage and the other endpoints in both untreated and drug-treated mice. CONCLUSIONS: WR-151327 has the potential to protect against radiation-induced late normal tissue damage.

Animals↗

PubMed1994

Chromosome terminal deletion formation in Chinese hamster ovary cells.

To investigate the fate of unrejoined DNA double-strand breaks, the frequency of 60Co gamma-ray- and restriction-enzyme-induced terminal chromosome deletions, a marker of unrejoined breaks, was determined in CHO-K1 and in xrs-5 cells. The xrs-5 cell is a DNA double-strand break repair-deficient derivative of CHO-K1. Terminal deletion frequency was small in both CHO-K1 and xrs-5 cells when cells were irradiated or treated with restriction enzyme while in the G1 phase of the cell cycle. In contrast, previous studies have shown that treatment of cells in G2 leads to large deletion frequencies, especially in xrs-5 cells. Cell cycle analyses show large G2 blocks in irradiated xrs-5 cells with only partial recovery over a 24-96-h period. These results suggest that most CHO cells with unrejoined breaks are blocked in G2 and, therefore, do not contribute to chromosome mutation frequencies. The small frequencies of terminal deletions that are found in these cells may reflect either an inefficiency in the G2 checkpoint mechanism or, perhaps, a modification of broken ends that allows passage through G2.

Animals↗

PubMed1994

Transformation of human epidermal keratinocytes with fission neutrons.

The biological effects of exposures to high LET radiations have particular relevance to radiation protection and risk assessment. Since most cancers are of epithelial origin, it is important to obtain a better understanding of radiation-induced oncogenic transformation in this cell type. Accordingly we have initiated studies to determine whether immortalized human epidermal keratinocytes (RHEK) can be transformed with high LET radiations. Exponentially growing RHEK cells were treated with single doses (1, 10, 25, 50 and 100 cGy) of 0.85 MeV fission neutrons from the Janus reactor. Neutron exposure led to the development of morphologically altered cells and foci formation after 6 weeks at confluence. These transformed cultures grew with an increased saturation density, exhibited anchorage-independent growth and formed tumors in athymic mice. Single-strand conformational polymorphism analysis and DNA sequencing demonstrated the absence of point mutations in codons 12/13 and 61 in the Ha-ras, Ki-ras, or N-ras genes and exons 4-9 of the p53 tumor suppressor gene. These studies demonstrate that high LET radiations (fission neutrons) can transform immortalized human epithelial cells to a malignant phenotype that does not appear to involve mutations in either the cellular p53 or ras genes.

Animals↗

PubMed1994

Protection against radiation-induced mutagenesis at the hprt locus by spermine and N,N"-(dithiodi-2,1-ethanediyl)bis-1,3-propanediamine (WR-33278).

The polyamine spermine and the disulfide N,N"-(dithiodi-2,1-ethanediyl)bis-1,3-propanediamine (WR-33278) are structurally similar agents capable of binding to DNA. WR-33278 is the disulfide moiety of the clinically studied radioprotective agent S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721). Because of their reported structural and functional similarities, it was of interest to compare their effects on cell survival and mutation induction at the hypoxanthine-guanine phosphoribosyl transferase (hprt) locus in Chinese hamster AA8 cells. WR-33278 and spermine (at concentrations of 0.01 and 0.001 mM) were electroporated into cells. Electroporation, 300 V and 125 microF, was performed either 30 min prior to or 3 h following exposure of cells to 750 cGy of ionizing radiation. Electroporation alone reduced cell survival to 75% but had no effect on hprt mutation frequency. The electroporation of either spermine or WR-33278 at concentrations greater than 0.01 mM was extremely toxic. The exposure of cells to both electroporation and irradiation gave rise to enhanced cell killing and mutation induction, with the sequence of irradiation followed 3 h later by electroporation being the more toxic protocol. Cell survival was only enhanced following electroporation of 0.01 mM of spermine and WR-33278 30 min prior to irradiation. Protection against radiation-induced hprt mutations was observed for both spermine and WR-33278 under all experimental conditions tested. Spermine at exposure concentrations of 0.01 and 0.001 mM administered 30 min before or 3 h after irradiation reduced mutation frequencies by factors of 2.2, 1.2, 1.9 and 2.2, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Varying levels of radioprotection from the effects of JANUS neutrons in repair-deficient xrs-5 hamster cells treated with azacytidine.

A series of cell lines have been generated from the radiation-sensitive Chinese hamster ovary line xrs-5 by treatment with azacytidine. Several of these lines have been shown to be resistant to gamma radiation. Survival curves have been generated for several of these lines and the parental lines after exposure to 0 to 5 Gy of JANUS neutrons in the presence or absence of a 30-min pretreatment with the aminothiol radioprotector WR-1065. These studies were performed to determine whether the parental xrs-5 cell line was radioresistant to exposure to JANUS neutrons and whether reversion to a neutron-resistant phenotype correlated with recovery of aminothiol radioprotection. Exposure to 4 mM WR-1065 enhanced survival after exposure to neutron radiation for most "revertant" lines, although the increase in survival varied. The xrs-5 cell line was sensitive to JANUS neutrons and showed no protection by WR-1065. These data indicate that xrs-5 cells are also sensitive to neutron radiation, that azacytidine-induced revertants for gamma-ray survival demonstrate the wild-type phenotype for survival after neutron exposure, and that the gene product that is defective is responsible for repairing only a small portion of neutron-induced damage.

Animals↗

PubMed1994

Inhibition of topoisomerase II alpha activity in CHO K1 cells by 2-[(aminopropyl)amino]ethanethiol (WR-1065).

The aminothiol 2-[(aminopropyl)amino]ethanethiol (WR-1065) is the active thiol of the clinically studied radioprotective agent S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721). WR-1065 is an effective radiation protector when it is administered 30 min prior to exposure of Chinese hamster ovary K1 cells to radiation (i.e., a dose modification factor of 1.4) at a concentration of 4 mM. Under these exposure conditions, topoisomerase (Topo) I and II alpha activities and associated protein contents were measured in cells of the K1 cell line using the DNA relaxation assay, the P4 unknotting assay and immunoblotting, respectively. WR-1065 was ineffective in modifying Topo I activity, but it did reduce Topo II alpha activity by an average of 50%. The magnitude of Topo II alpha protein content, however, was not affected by these exposure conditions. The effects on the cell cycle were monitored by the method of flow cytometry. Exposure of cells to 4 mM WR-1065 for up to 6 h resulted in a build-up of cells in the G2/M-phase compartment. However, under these conditions and in contrast to Topo II inhibitors used in chemotherapy, WR-1065 is an effective radioprotective agent capable of protecting against both radiation-induced cell lethality and mutagenesis. One of several mechanisms of action attributed to aminothiol compounds such as WR-1065 has been their ability to affect endogenous enzymatic reactions involved in DNA synthesis and repair and progression of cells through the phases of the cell cycle. These results are consistent with such a proposed mechanism and demonstrate in particular a modifying effect by WR-1065 on Topo II, which is involved in DNA synthesis.

Animals↗

PubMed1993

Induction of hprt mutations in mice after exposure to fission-spectrum neutrons or 60Co gamma rays.

The effects of exposure to fission-spectrum neutrons and 60Co gamma rays on mutation induction in B6CF1 mice were investigated. Mutation induction was measured at the hypoxanthine-phosphoribosyl-transferase (hprt) locus in splenic lymphocytes at 56 days after whole-body irradiation. Lymphocytes were cultured 12-16 days in round-bottomed, 96-microwell plates in the presence of 5 x 10(4) feeder cells (syngeneic lymphocytes irradiated with 50 Gy gamma rays). The selective agent used as 6-thioguanine at a concentration of 2.5 micrograms/ml. Animals were exposed to either single doses of neutrons (1.5 Gy) or photons (7.5 Gy) or fractionated doses delivered over 2 weeks of neutrons (0.25 Gy x 6, total 1.5 Gy) or photons (1.5 Gy x 6, total 9.0 Gy). The frequency of hprt mutant induction by fission-spectrum neutrons delivered in a 1.5-Gy single dose compared to a 7.5-Gy single dose of 60Co photons was approximately the same, i.e., 5.98 x 10(-5) +/- 1.51 x 10(-5) (SE) vs. 5.56 x 10(-5) +/- 3.09 x 10(-5) (SE), respectively (Student's two-tailed t test, P = 0.8997). Multiple doses of neutrons gave rise to slightly higher mutant frequencies compared to photons even though the ratio of total doses of neutrons to photons was increased from 5 to 6, i.e., 8.71 x 10(-5) +/- 5.39 x 10(-5) (SE), total dose 1.5 Gy, vs 2.30 x 10(-5) +/- 9.07 x 10(-6) (SE), total dose 9.0 Gy, respectively (Student's two-tailed t test, P = 0.3330). These results suggest that the relative differences in magnitude in radiation-induced genotoxic effects between fission-spectrum neutrons and 60Co gamma rays increase when the comparisons are made between fractionated rather than single-dose exposure regimens.

Animals↗

PubMed1992

Analysis of ascites from patients with ovarian carcinoma by cell flow cytometry.

Cell flow cytometry offers the opportunity to analyze cytopathological samples with regards to DNA content and proliferative activity. To investigate whether this modality can quantitate certain aspects of ovarian carcinoma by analyzing ascites, 43 samples from patients with advanced papillary serous adenocarcinoma of the ovary were studied. In 28 samples (65%) ploidy and the percentage of cells in S phase (%S phase) could be analyzed. Fifteen samples could not be analyzed because of overlapping cell populations distorting distinct cell cycle phases. Of the 28 samples studied, 8 (29%) were diploid and 20 (71%) were aneuploid. The DNA in aneuploid samples ranged from 1.23 to 2.65. The %S phase for aneuploid was greater than that for diploid samples. Patients with diploid samples survived longer. Cytometric analysis of cells from ascites in 4 patients in whom disease progressed after they received chemotherapy showed that the percentage of cells in S phase increased. Cells from ascites established in vitro showed that ploidy and proliferative activity changed as cells were passed in culture. In conclusion, the analysis of ascites by cell flow cytometry may be a prognosticator in patients with advanced ovarian carcinoma. In addition, conclusions extrapolated from in vitro data to the in vivo situation should be done cautiously since late-passaged cells may not always be representative of the initial tumor sample.

Aneuploidy↗

PubMed1992

Protection by WR-2721 and WR-151327 against late effects of gamma rays and neutrons.

Two thiophosphoroate compounds WR-2721 and WR-151327 were assessed for their ability to modify the deleterious effects (life shortening and carcinogenesis) of fission-spectrum neutrons (kerma-weighted mean energy of 0.85 MeV) or gamma rays on B6CF1 hybrid mice. Male and female mice, 200 of each sex per experimental group, were irradiated individually at 110 days of age. Radioprotectors (400 mg/kg of WR-2721 or 580 mg/kg of WR-151327) were administered intraperitoneally 30 min prior to irradiation. Neutron doses were 10 cGy or 40 cGy and gamma ray doses were 206 cGy or 417 cGy. Animals were housed five to a cage; cage locations in the holding rooms were randomized by computer. Animals were checked daily and all deceased animals were necropsied. WR-2721 afforded protection against both neutron- and gamma-ray-induced carcinogenesis and subsequent life shortening. Cumulative survival curves for unirradiated mice of either sex were unaffectecd by protectors. WR-2721 protected irradiated groups against life shortening by approximately 10 cGy of neutrons or 100 cGy of gamma rays. WR-151327 was as effective as WR-2721 against neutron irradiation.

Amifostine↗

PubMed1992

Protection against AZT-induced mutagenesis at the HGPRT locus in a human cell line by WR-151326.

The anti-AIDS agent, AZT (3'-azido-3'-deoxythymidine), is mutagenic in a cultured human hepatoma cell line designated HepG2 at the HGPRT (hypoxanthine-guanine phosphoribosyl transferase) locus. Using an exposure time of 3 hr, the number of mutants per 10(6) surviving cells increased as a function of AZT dose from 125 to 520. Chinese hamster ovary cells, in contrast, are not affected with respect to this endpoint when similar concentrations of AZT are used (i.e., 0.1 to 10 mg/ml). The aminothiol WR-151326 [3-(3-methylaminopropylamino) propanethiol dihydrochloride] was evaluated as a possible antimutagen for use with AZT. At a concentration of 4 mM, WR-151326 was added either concomitantly or following exposure of HepG2 cells to a 5 mg/ml concentration of AZT. Regardless of the treatment condition, WR-151326 was effective in reducing the mutagenic effects of AZT by about a factor of 2. Correcting for background mutations, the mutation frequencies determined were: AZT only for 3 hr, 110 x 10(-6) (S.E.M. +/- 6.0 x 10(-6)); AZT together with WR-151326 for 3 hr, 57 x 10(-6) (S.E.M. +/- 3.0 x 10(-6)); and AZT for 3 hr followed by WR-151326 for 3 hr, 68 x 10(-6) (S.E.M. +/- 5.0 x 10(-6)). This study demonstrates that AZT is mutagenic to a cell line of human origin and that WR-151326 can protect against this mutagenic process.

Humans↗

PubMed1992

Reversion of radiosensitivity in azacytidine-treated XRS5 cells does not result in full radioprotection by WR-1065.

A series of cell lines were previously generated from the radiation sensitive Chinese hamster ovary line xrs5 after treatment with azacytidine. Six of these lines have been examined for their resistance to killing by 0 to 20 Gray of 60Co gamma rays and the amount of radioprotection afforded by treatment with the drug 2-[(aminopropyl)amino]ethanethiol (WR-1065). As xrs5 cells have lost the ability to be protected by WR-1065, studies were performed to determine whether reversion to radio-resistance correlated with recovery of aminothiol radioprotection. Treatment of azacytidine-treated, radiation sensitive and resistant cells with four millimolar WR-1065 30 minutes prior to irradiation enhanced survival after exposure to gamma radiation, although the enhancement in survival was less than for wild type Chinese hamster ovary K1 cells. The data suggest that there is not an absolute linkage between recovery of gamma ray radiation resistance and protection by WR-1065 and other factors, such as chromatin organization, must play a role.

Animals↗

PubMed1992

Antimutagenic effects of radioprotector WR-2721 against fission-spectrum neurons and 60Co gamma-rays in mice.

The antimutagenic effects of the radiation protective agent, S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721), were studied against fission-spectrum-neutron- and 60Co-gamma-ray-induced mutagenesis in mice. Mutagenesis at the hypoxanthine-guanine phosphoribosyl transferase (hprt) locus was measured 56 days following whole-body irradiation with JANUS neutrons (single doses, 50-150 cGy) or 60Co photons (single doses, 250-750 cGy). Splenic T lymphocytes from B6CF1 mice were grown in round-bottomed 96-microwell culture plates with or without the selective agent 6-thioguanine (6-TG). The mutant frequency, as a result of exposure to neutrons or 60Co photons, increased 100-fold with dose. Doses of 150 cGy neutrons and 750 cGy 60Co photons were equally mutagenic. When animals were injected with WR-2721 at a dose of 400 mg/kg body weight, i.p., 30 min before whole-body irradiation with JANUS neutrons or 60Co photons, mutant frequencies were significantly reduced at all radiation doses (i.e. protection factors of 1.4 and 2.4, respectively). Thus, the aminothiols are effective antimutagens. A novel clinical application of these compounds could be in their use to protect against radiation- and/or chemotherapy-induced genotoxic damage to normal cells.

Amifostine↗

PubMed1992

In vivo protection by the aminothiol WR-2721 against neutron-induced carcinogenesis.

The ability of the compound S-2-(aminopropylamino)ethylphosphorothioic acid, designated WR-2721, to protect against neutron-induced carcinogenesis was investigated. Both sexes of the B6CF1 mouse were injected i.p. with 400 mg/kg of WR-2721 30 min prior to being irradiated by 10 cGy of neutrons. Neoplastic mortality in the groups receiving thiol was either reduced or delayed relative to irradiated mice not given protector. However, the time at which the protective effect of WR-2721 was expressed depended on the sex of the animal. Thiol-related shifts in the time of neoplastic death in females occurred only in the first half of the lifespan. Once a female survived to the mean age at death, no difference in the pattern of mortality could be detected between control and WR-2721-treated mice exposed to neutrons. Irrespective of thiol treatment, the timing of tumour-related death was nearly identical during the first half of life for males exposed to neutrons. In the last half of the lifespan, survival of thiol-protected males was enhanced relative to saline-injected males and even exceeded that observed in the control population.

Amifostine↗

PubMed1992

The radioprotector WR-2721 reduces neutron-induced mutations at the hypoxanthine-guanine phosphoribosyl transferase locus in mouse splenocytes when administered prior to or following irradiation.

An in vitro T-lymphocyte cloning technique has been applied to study the effects of JANUS fission-spectrum neutron irradiation and the radioprotector S-2-(3-aminopropylamino) ethylphosphorothioic acid (WR-2721) on the subsequent development of somatic mutations at the hypoxanthine-guanine phosphoribosyl transferase (hprt) locus in hybrid B6CF1 male mice. In control studies performed to establish an in vitro cloning technique, the mutant frequencies of splenic T-lymphocytes, as a result of exposure to a 100 cGy dose of neutrons, increased with time from a control level of 9 x 10(-7) to a maximum value of 1.7 x 10(-5) at 56 days following irradiation. Between 56 and 150 days after irradiation, mutant frequencies were observed to plateau and remain stable. All subsequent determinations were performed at 56 days following the experimental treatment of animals. WR-2721 at a dose of 400 mg/kg was effective in protecting against the induction of hprt mutants (i.e. a mutant frequency reduction factor, MFRF) following the largest dose of neutrons used (i.e. 150 cGy), whether it was administered i.p. 30 min before, 5 min after, 3 h after, or three times at 3, 24, and 48 h after, as evidenced by MFRFs of 6.0, 6.6, 4.8 and 5.8 respectively. The antimutagenic effectiveness of WR-2721 administered 30 min prior to irradiation was unaffected, even when the dose was reduced to 200 mg/kg, MFRF = 7.0; 100 mg/kg, MFRF = 3.8; and 50 mg/kg, MFRF = 8.9. These findings confirm our earlier report using the radioprotector N-(2-mercaptoethyl)-1,3-diaminopropane (WR-1065) under in vitro conditions, and demonstrate that these agents can be used as effective antimutagens even when they are administered up to 3 h following radiation exposure.

Amifostine↗

PubMed1992

Chemical protection and cell-cycle effects on radiation-induced mutagenesis.

Chinese hamster ovary cells in the exponential phase of growth were harvested and separated by the method of centrifugal elutriation into subpopulations enriched with up to 95% G1 phase, 70% S phase and 65% G2 + M phase cells. Cell cycle distributions were routinely monitored by flow cytometry. Following elutriation, aliquots of cells from each of the enriched cell fractions were incubated in the presence or absence of 4 mM of 2-[(aminopropyl)amino] ethanethiol (WR-1065) for 30 min at 37 degrees C. The cells were then irradiated with 60Co gamma-rays or fission-spectrum neutrons from the JANUS research reactor. Both cell killing and mutagenesis were determined. Regardless of the radiation quality used, cells enriched in G1 phase were the most sensitive to radiation-induced mutagenesis at the hypoxanthine-guanine phosphoribosyl transferase locus. The relative magnitude of protection exerted by WR-1065 differed for each of the elutriator separated cell populations. The greatest magnitude of protection, however, was observed for G1-enriched populations, regardless of the radiation quality used or the biological end-point tested.

Animals↗

PubMed1992

Effects of growth media on cell cycle progression in CHO cells exposed to the radioprotector WR-1065.

WR-1065 (2-[(aminopropyl)amino]ethanethiol) reduces cytotoxic and mutagenic effects caused by exposure of cells to radiation and chemotherapeutic drugs, but the mechanisms involved are not fully known. We have observed an accumulation of cells in G2 in WR-1065 treated Chinese hamster ovary cells grown in alpha-minimal essential medium, while others have found no cell cycle effects in WR-1065 treated Chinese hamster ovary cells grown in McCoy's 5A medium. To determine if the two types of media had an effect on cells treated with WR-1065, we examined survival and cell cycle progression. Population doubling times of 12 h were observed for cells grown in both media. Incubation of AA8 cells grown in McCoy's 5A medium with 4 mM WR-1065 30 min prior to and during irradiation with 137Cs gamma-rays resulted in a protection factor of 2.2, in close agreement with the value of 2.0 we previously obtained for AA8 cells grown in alpha-minimal essential medium. Treatment with WR-1065 caused an alteration in the cell cycles of cells grown in both media. An increase in the G2 population and a decrease in the G1 population was observed in cells incubated up to 3 h in the presence of 4 mM WR-1065, with a redistribution of the cells throughout the cell cycle occurring following removal of the drug. These data suggest that exposure of cells to WR-1065 is the cause of perturbations in cell cycle progression, and is not affected by the type of medium the cells are grown in.

Animals↗

PubMed1991

Protection against late effects of radiation by S-2-(3-aminopropylamino)-ethylphosphorothioic acid.

We have demonstrated that S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR2721) administered to mice 30 min prior to a relatively low dose of ionizing radiation is effective in protecting against radiation-induced carcinogenesis and subsequent life shortening. Female C57BL/6JANL x BALB/cJANL F1 mice, 200 per group, were exposed to gamma radiation at a dose of 206 cGy. Additional groups of 200 animals were sham treated, given injections of 400 mg/kg of WR2721, or administered WR2721 and the irradiated with 60Co photons at doses of 206 cGy or 417 cGy. Mice were treated at 110 days of age. They were housed five to a cage and were checked daily throughout life. All deceased animals were necropsied, and tissues were removed and fixed for histopathological analysis. Over 90% of the animal deaths were due to tumor involvement. WR2721 afforded significant protection (P = 0.0016) against radiation-induced malignancies (i.e., a total of 164 tumor codes were used) following a dose of 206 cGy. Protection against lymphoreticular tumors in particular was significant (P = 0.0165). Subsequent survival time in WR2721-protected animals (compared with matched irradiated controls) was extended by 65 days. Mice irradiated with 417 cGy following administration of WR2721 exhibited a response similar to those irradiated without the protector at a dose of 206 cGy (P = 0.26). Cumulative survival curves for unirradiated mice were unaffected by a single dose of WR2721. These data indicate a potential novel benefit for radioprotectors in cancer therapy. WR2721 and similar aminothiols may be effective adjuvants for reducing the risk of therapy-induced secondary cancers in patients who have an excellent prognosis for cure and long-term survival.

Amifostine↗