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PubMed2001

Lens epithelial cell protection by aminothiol WR-1065 and anetholedithiolethione from ionizing radiation.

Lens epithelium disorganization, glutathione (GSH) depletion, and epithelial cell death have been incriminated in the cytopathogenic mechanisms that lead to cataract formation following UVB and x-ray exposures. The objective of this study was to determine the in vitro capacity of the aminothiol WR-1065, the active metabolite of amifostine, and anetholedithiolethione (ADT or Sulfarlem) to protect bovine lens epithelial cells against x-ray irradiation. WR-1065 and ADT were used at a concentration of 20 microM. A single dose of 10 Gy was delivered at a rate of 2 Gy/min. Fluorimetric assays were then performed using a neutral red probe to evaluate cell viability, a Hoechst 33342 probe (HO) to evaluate nuclear condensation and apoptosis, and a monobromobimane probe to estimate the intracellular GSH pool. Twenty-four hours after x-ray exposure, cells pretreated with WR-1065 showed increased GSH levels, improved cell viability, and decreased HO fluorescence in addition to a lesser proportion of cells with apoptotic nuclear modifications. Between 72 and 120 hr postirradiation, ADT-pretreated cells also showed increased intracellular GSH levels and cell viability and decreased HO fluorescence and apoptotic cell morphology. This in vitro study demonstrates that WR-1065 and ADT protects lens epithelial cells from x-ray injury; thus, ADT and amifostine are appropriate candidates for clinical trials in humans. They are currently used in preventing radiation-induced xerostomia and should be further tested in the prevention of late radiation-induced ocular complications such as sicca syndrome and cataract.

Amifostine↗
PubMed2002

Inhibition of spontaneous metastases formation by amifostine.

Amifostine was investigated for its ability to inhibit spontaneous metastases formation using the well-characterized murine sarcoma, Sa-NH. Amifostine was administered intraperitoneally at a dose of 50 mg/kg every other day for 6 days to C3Hf/Kam mice until tumors reached an average size of 8-8.5 mm in diameter. Amifostine was again administered immediately after surgical removal of the tumor-bearing limbs by amputation, and then once more 2 days later. Twenty-one days later, animals were evaluated for the presence of spontaneously developed pulmonary metastases. Nontumor-bearing control animals were sham treated using the same dosing and surgery schedules. Treatment with amifostine appeared to slightly delay tumor growth, that is, 13 vs. 12 days for tumors to reach an average diameter of 8 mm. Amifostine reduced both the incidence of pulmonary metastases formed in experimental animals from 77% to 57% (p < 0.05), and their average number per animal from 12.8 +/- 5.4 (SEM) to 2.9 +/- 1.1 (SEM). The effect of amifostine exposure on serum levels of the angiogenesis inhibitor angiostatin was also determined using Western blot analysis. Consistent with the antimetastatic effect, exposure of animals to 50 mg/kg of amifostine resulted in a 4-fold enhanced serum level of angiostatin above control levels. This phenomenon occurred in tumor-bearing and nontumor-bearing animals. The effects of amifostine on matrix metalloproteinase (MMP) enzymatic activity was also determined using gelatin zymography. Conditioned growth medium collected from Sa-NH cells grown to confluency was exposed to various concentrations of SH, i.e., 2-[(aminopropyl)amino]ethane-thiol (WR-1065), the active thiol form of amifostine, for either 30 min or 18 hr. WR-1065, as a function of increasing dose and time, inhibited the enzymatic activities of MMP-2 and MMP-9. At a concentration and time of exposure likely to be achieved in vivo, that is, 40 microM and 30 min, MMP-2 and MMP-9 activities were reduced to between 30% and 40% of control values. Consistent with these affects, WR-1065 was also found to be effective in inhibiting the ability of Sa-NH cells to migrate through Matrigel membranes. After an 18-hr exposure under in vitro conditions, WR-1065 at concentrations of 4, 40 and 400 microM, and 4 mM, inhibited Sa-NH migration to 11%, 44%, 81% and 97% of control values, respectively. The abilities of amifostine and its active thiol WR-1065 to stimulate angiostatin production in mice, and to inhibit the MMP enzymatic activities and invasion ability of Sa-NH cells under in vitro conditions, are consistent with the observed antimetastatic effects exhibited against Sa-NH tumors growing in vivo.

Amifostine↗
PubMed1996

Hypotensive mechanisms of amifostine.

Amifostine, a chemo- and radioprotective agent developed as adjunctive therapy for malignancies, induces hypotension after approximately 20% of patient administrations. This study examines the molecular mechanisms underlying hypotension induced by amifostine. Amifostine and its metabolite, WR-1065, induced dose-dependent hypotension in anesthetized rats that was not blocked by N(G)-methyl L arginine (L-NAME), an NO synthase inhibitor. WR-1065 but not amifostine induced concentration-dependent relaxation of isolated rat aortic rings in an endothelium-independent fashion. Relaxation was not associated with increases in cGMP or cAMP and could not be blocked by L-NAME or indomethacin. Similarly, neither amifostine or WR-1065 activated adenylyl, particulate guanylyl, or soluble guanylyl cyclases. WR-1065 relaxed rat aortic rings precontracted with norepinepherine, suggesting alpha-adrenergic blocking activity. However, neither amifostine nor WR-1065 altered the ability of prazosin or phentolamine to bind to alpha-adrenergic receptors. Further, WR-1065 had no effect on receptor-mediated increases in intracellular calcium in BAL 17 murine B lymphocytes in vitro. Thus, hypotension after administration of amifostine is mediated by WR-1065 and appears to result from direct relaxation of vascular smooth muscle. Smooth muscle relaxation induced by WR-1065 is not related to production of nitric oxide, prostaglandins, or cyclic nucleotides; alpha-adrenergic receptor antagonism; or interference with receptor-dependent increases in intracellular calcium. Administration of ephedrine, an efficacious adrenergic agonist, attenuated hypotension induced by amifostine in anesthetized rats and may be useful in alleviating hypotension associated with amifostine administration in patients.

Adrenergic Agents↗
PubMed2002

Restoration of wild-type conformation and activity of a temperature-sensitive mutant of p53 (p53(V272M)) by the cytoprotective aminothiol WR1065 in the esophageal cancer cell line TE-1.

The aminothiol WR1065, the active metabolite of the cytoprotector amifostine, exerts its antimutagenic effects through free-radical scavenging and other unknown mechanisms. In an earlier report, we showed that WR1065 activates wild-type p53 in MCF-7 cells, leading to p53-dependent arrest in the G(1) phase of the cell cycle. To determine whether WR1065 activates p53 by modulating protein conformation, we analyzed its effects on p53 conformation and activity in the esophageal cancer cell line TE-1. This cell line contains a mutation in codon 272 of p53 (p53(V272M), with methionine instead of a valine), conferring temperature-sensitive properties to the p53 protein. At the nonpermissive temperature (37 degrees C), p53(V272M) adopts the mutant p53 conformation (nonreactive with the antibody PAb1620), does not bind specifically to DNA, and is not activated in response to DNA-damaging treatment. However, treatment with 0.5-4 mM WR1065 partially restored wild-type conformation at 37 degrees C, stimulated DNA binding activity, and increased the expression of p53 target genes WAF-1, GADD45, and MDM2, leading to cell-cycle arrest in G(1). These results suggest that WR1065 activates p53 through a mechanism distinct from DNA-damage signaling, which involves modulation of p53 protein conformation.

Cell Cycle↗
PubMed1996

Induction of cell death by cytokines in cell cycle-synchronous tumor cell populations restricted to G1 and G2.

In the present work, cytokine-mediated induction of cell death was investigated by flow cytometry in cell cycle-synchronous human tumor cell populations gained by centrifugal elutriation or by cell cycle blockade with mimosine and aphidicolin. Attention was payed to the question of whether the effector phase of cell death takes place in the same phase of the cell cycle in which the death signal is received. Another point of interest was the question whether synchronization of cell populations with respect to the cell cycle leads to increased synchronicity of the death phase. The results demonstrate that supernatants from monocyte/tumor cell interaction cultures containing tumor necrosis factor-alpha, interferons, and interleukins-1 and -6 or appropriate combinations of pure cytokines cause cell cycle arrest predominantly in G1 and to a lesser extent in G2. Cell death is initiated from both arrest points. Cytokine-treated G1 cells do not enter S phase. They die within the same G1 phase in which they receive the death signal. In contrast, a high proportion of cytokine-treated G2 cells pass through mitosis and are arrested and die in the subsequent G1 phase, whereas only a smaller proportion of cells are arrested and die in G2. The synchronicity of the death phase cannot be increased by the diverse methods of cell cycle synchronization applied. Interestingly, aurintricarboxylic acid, an agent known for inhibitory effects on nucleolytic activities and other protein/nucleic acid interactions, not only prevents cell death, but also cell cycle arrest.

Aphidicolin↗
PubMed1995

Modulation of bleomycin-induced mitotic recombination in yeast by the aminothiols cysteamine and WR-1065.

The cancer chemotherapy drug bleomycin (BLM) is a potent inducer of genetic damage in a wide variety of assays. The radioprotectors cysteamine (CSM) and WR-1065 have been shown in previous studies to potentiate the induction of micronuclei and chromosome aberrations by BLM in Go human lymphocytes. By contrast, WR-1065 is reported to reduce the induction of hprt mutations by BLM in Chinese hamster cells. To elucidate the basis for these interactions, we examined the effects of CSM and WR-1065 on the induction of mitotic gene conversion by BLM in the yeast Saccharomyces cerevisiae. Treatment with BLM causes a dose-dependent increase in the frequency of mitotic gene conversion and gene mutations. Unlike its potentiation of BLM in Go lymphocytes, WR-1065 protected against the recombinagenicity of BLM in yeast. CSM was also strongly-antirecombinagenic under, some conditions, but the nature of the interaction depended strongly on the treatment conditions. Under hypoxic conditions, cysteamine protected against BLM, but under oxygen-rich conditions CSM potentiated the genetic activity of BLM. The protective effect of aminothiols against BLM may be ascribed to the depletion of oxygen required for the activation of BLM and the processing of BLM-induced damage. Aminothiols may potentiate the effect of BLM by acting as an electron source for the activation of BLM and/or by causing conformational alterations that make DNA more accessible to BLM. The results indicate that aminothiols have a strong modulating influence on the genotoxicity of BLM in yeast as they do in other genetic assays. Moreover, the modulation differs markedly depending on physiological conditions. Thus, yeast assays help to explain why aminothiols have been observed to potentiate BLM in some genetic systems and to protect against it in others.

Alleles↗
PubMed1992

The reversal of cisplatin-protein interactions by the modulating agent WR2721 and its metabolites WR1065 and WR33278.

The reversibility of cisplatin-protein interactions by the modulating agent WR2721, its active thiol-metabolite WR1065, and the symmetrical disulfide WR33278 was studied using the model compounds (Pt(diethylenetriammine) monofunctionally bound to the sulfur in glutathione (Pt(dien)SG) and Pt(diethylenetriammine) monofunctionally bound to the sulfur in S-methylglutathione (Pt(dien)SMeG). Both model compounds could be quantified by high-performance liquid chromatography (HPLC) with UV detection. The Pt-cysteine-like bond in Pt(dien)SG could not be reversed by any of the WR compounds or by the strong nucleophiles thiosulfate (TS) and diethyldithiocarbamate (DDTC). However, the Pt-methionine-like bond in Pt(dien)SMeG could be reversed by WR1065, although the reversal was slow (k2 = 0.142 M-1 s-1) as compared with that obtained using the modulating agents TS (k2 = 10.1 M-1 s-1) and DDTC (k2 = 3.66 M-1 s-1). WR2721 was hardly able to reverse the Pt-S bond in Pt(dien)SMeG (k2 = 0.00529 M-1 s-1), and WR33278 showed no capacity to do so. The activity of cis-diamminedichloroplatinum(II) (CDDP)-inactivated fumarase was not appreciably restored by any of the WR compounds (16%, 7.7%, and 0 for 20 mM WR1065, WR2721, and WR33278, respectively) in contrast to the strong nucleophile DDTC (61% for 2 mM DDTC). These in vitro studies provide information at the molecular level that may explain why WR2721, in contrast to DDTC, does not provide protection against cisplatin-induced nephrotoxicity when it is given after platinum-containing chemotherapy. The results support the present clinical use of WR2721 prior to the administration of platinum compounds.

Amifostine↗
PubMed1991

Experimental basis for increasing the therapeutic index of carboplatin in brain tumor therapy by pretreatment with WR compounds.

We tested an experimental strategy to decrease the dose-limiting hematotoxicity of carboplatin without compromising its activity against brain tumors. The effect of pretreatment with WR-1065, a chemomodifier that penetrates brain poorly, on carboplatin's cytotoxicity was evaluated in human hematopoietic granulocyte-monocyte progenitor cells and in three human glioblastoma cell lines. WR-1065 reduced bone marrow toxicity without decreasing carboplatin's activity against glioblastoma cells. These results suggest that the therapeutic index of carboplatin might be increased in the treatment of malignant brain tumors.

Bone Marrow↗
PubMed1978

Repair and biochemical protection in life shortening of mice exposed to fractionated X-irradiation.

Male mice of the BALB/c+ strain were exposed to X-rays at fractionation intervals of 7, 15, 30, and 60 days. One group received a mixture of radioprotectors, another AET (only 30 days fractionation), a third one served as control. The doses ranged, dependent on the treatment, from 300--1500 R. When survival was corrected for acute death, the control and AET treated animals died after an accumulated dose of about 2000 R whereas those treated with a mixture of radioprotectors died after about 4000 tr. Bone marrow failure and lung damage is the main cause of death within the initial 200 days after start of the exposure. At later times, fibrotic changes and in particular glomerulosclerosis are observed.

Animals↗