Equitoxic Levels Research Articles

Current Perspectives on Proton Therapy: Techniques Shaping the Future of Cancer Treatment

Traditional Radiation Therapy (RT) predominantly comprises a targeted therapeutic strategy focused on improving localised tumour control and achieving a cure while minimising the occurrence of adverse side effects. It could be feasible to take advantage of the better dose distribution by enabling larger RT dosages to the malignancy while preventing a rise in the toxicity of RT-induced healthy tissue, or by reducing adverse reactions to manageable levels. Poor local disease control and important dose-limiting normal tissue, which prevent safe dosage increase with conventional photon RT, have been the key justifications for RT. Proton treatment, on the other hand, delivers therapeutic protons or positive particles using proton beams. The potential advantage of protons’ physical properties allows for more localised RT delivery. By increasing the dosage to equitoxic levels, it is also possible to take advantage of the potential improvement in normal tissue sparing to support local tumour management and, ideally, longevity. Proton treatment preserves more important structures than photon therapy because of its unique physics. Thus, there is a need for wide usage of Proton Therapy (PT) for successive cancer treatment. The present review focuses on PT based on tumour site, clinical studies, biological barriers, instrumentation of PT, significance, and limitations.

INDIVIDUAL AND EQUITOXIC EFFECTS OF COPPER AND CADMIUM ON BEHAVIOURAL RESPONSES AND SURVIVAL IN CARP, LABEO ROHITA (HAMILTON, 1822)

Acute toxicity of copper, cadmium individually and in combinations of Cu + Cd were studied in carp, Labeorohitaas a function of time. Mortality of fish was dependent on dose of metal exposures and exposure period. The behavioural changes of L. rohitawere found to be different when exposed to Cu and Cd individually and in combinations. It was more pronounced in test animals exposed to equitoxic levels of Cu + Cd followed by individual exposures of Cu and Cd, while it was completely absent in the control fish. The 96 hr median lethal concentration of copper, cadmium and combination of both in L. rohitawas 0.42, 0.78 and 0.39 ppm respectively. Similar trend was observed in 24, 48 and 72 hrs also. It manifests that Cu + Cd combination was more toxic than any one of the single metal solutions tested

Comparative investigation of multiple organs of mice and rats in the comet assay

Mice and/or rats are usually used to detect chemical carcinogenicity and it has been known that there are species differences in carcinogenicity. To know whether there are species difference in genotoxicity, we conducted comparative investigation of multiple organs of mice and rats in the comet assay. Since the sensitivity to xenobiotics is different for different species, we queried species difference in the genotoxic sensitivity at one equitoxic level but not at one equidose. Therefore, groups of four mice or rats were treated once intraperitoneally or orally with a chemical at highest dose without death and distinct toxic manifestation. When the death was not observed at 2000 mg/kg of a chemical, 2000 mg/kg was used for the comet study. The stomach, colon, liver, kidney, bladder, lung, brain, and bone marrow were sampled 3, 8, and 24 h after treatment. Among chemicals tested, benzyl acetate, chlorodibromomethane and p-chloro- o-toluidine are carcinogenic to mice but not rats, and aniline, azobenzene, o-phenylphenol Na, and d-limonene are carcinogenic to rats but not mice. Although the two species differed in genotoxicity target organs and migration values, the judgement of a positive or negative response was the same for all chemicals studied except for 2,4-dimethoxyaniline, 2,5-diaminotoluene, and p, p′-DDT when chemicals with positive responses in at least one organ are judged to be comet assay-positive. 2,4-Dimethoxyaniline and 2,5-diaminotoluene that are Ames test-positive non-carcinogens in both species were positive in one organ (urinary bladder for 2,4-dimethoxyaniline and stomach for 2,5-diaminotoluene) in rats, but negative in all mouse organs. p, p′-DDT, which is an Ames test-negative but in vitro cytogenetic test-positive hepatic carcinogen in mice and rats, was positive in multiple rat organs, but not in any mouse organ. These results suggest that species differences in genotoxicity at one equitoxic level are not consistent with species difference in carcinogenicity and that the use of both species is appropriate to indicate a carcinogenic potential in the comet assay with multiple organs, when chemicals being positive in at least one organ are judged to be comet assay-positive.

Cisplatin and taxol activate different signal pathways regulating cellular injury-induced expression of GADD153

Signal transduction pathways activated by injury play a central role in coordinating the cellular responses that determine whether a cell survives or dies. GADD153 expression increases markedly in response to some types of cellular injury and the product of this gene causes cell cycle arrest. Using induction of GADD153 as a model, we have investigated the activation of the cellular injury response after treatment with taxol and cisplatin (cDDP). Activation of the GADD153 promoter coupled to the luciferase gene and transfected into human ovarian carcinoma 2008 cells correlated well with the increase in endogenous GADD153 mRNA after treatment with taxol but not after treatment with cDDP. Following treatment with cDDP, the increase in endogenous GADD153 mRNA was 10-fold greater than the increase in GADD153 promoter activity. Likewise, at equitoxic levels of exposure (IC80), cDDP produced a 5-fold greater increase in endogenous GADD153 mRNA than taxol. The tyrosine kinase inhibitor tyrophostin B46 had no significant effect on the ability of taxol to activate the GADD153 promoter, but inhibited activation of the GADD153 promoter by cDDP in a concentration-dependent manner. Tyrphostin B46 synergistically enhanced the cytotoxicity of cisplatin; however, the same exposure had no significant effect on the cytotoxicity of taxol. We conclude that (1) taxol and cDDP activate GADD153 promoter activity through different mechanisms; (2) the signal transduction pathway mediating induction by cDDP involves a tyrosine kinase inhibitable by tyrphostin B46; and (3) that inhibition of this signal transduction pathway by tyrphostin synergistically enhances cDDP toxicity.

DRUG-INDUCED ENDOTHELIAL INJURY POTENTIATES LUNG COLONIZATION IN A MURINE FIBROSARCOMA MODEL

Lung colonization induced by the intravenous injection of fibrosarcoma cells into syngeneic mice was enhanced by the pretreatment of mice with cyclophosphamide (CPA), adriamycin (ADM), cis-diammine-dichloroplatinum II (DDP) and methotrexate (MTX). At equitoxic levels, CPA showed greater enhancement of the lung colonization than the other drugs treated. After a two-hour pretreatment of an endothelial monolayer culture, the adhesion of fibrosarcoma cells to endothelial cells was enhanced by all drugs, and the greatest enhancement was obtained with CPA. Data from these experiments supports the hypothesis that endothelial cell damag by anticancer drugs may facilitate metastasis of circulating tumor cells.

Comparison of the Effects of Intra-Arterial and Intravenous Cisplatin on Both Limb Tumor and Lung Metastases of Transitional Cell Carcinoma RBT-1 in Rats

The effects of intra-arterial (i.a.) and intravenous (i.v.) cisplatin on both limb tumor and lung metastases of transitional cell carcinoma RBT-1 in rats were compared. Tumor weights of limb tumors and the amount of lung nodules were evaluated on the eighth day after chemotherapy experiments. Both cisplatin 5 mg/kg i.a. and 5 mg/kg i.v. were administered to rats, but the intra-arterial method showed a significantly better effect on the limb tumor, whereas the intravenous method tended to be more effective on the lung metastases. Using the same dosage (5 mg/kg), the intra-arterial cisplatin group demonstrated a weaker level of nephrotoxicity and a smaller loss of body weight than seen in the intravenous cisplatin group. When a higher dose of cisplatin (6 mg/kg) was administered in the intra-arterial group, the antitumor effect on lung metastases and nephrotoxicity were similar to those of the group given cisplatin 5 mg/kg i.v. These data suggest that the dose of intra-arterial cisplatin can be slightly higher than that of intravenous cisplatin. Subsequently, a similar antitumor effect on lung metastases and a significantly better antitumor effect on primary tumor may be obtained at the equitoxic level.

Reduced formation of lesions in the DNA of a multidrug-resistant L1210 subline selected for teniposide resistance

Earlier studies have suggested that higher cellular levels of teniposide (VM-26) are required for the inhibition of growth in L1210/VM-26 sublines than in parental L1210 cells. On the basis of this observation, we hypothesized that resistance to VM-26, which is partly attributed to multidrug resistance, also resulted in reduced formation of DNA lesions by the drug. In confirmation of this hypothesis, equitoxic concentrations of VM-26 produced fewer breaks in the DNA of LIa5 microM cells, the prototype L1210/VM-26 subline, than in that of L1210 cells. Previously, potassium cyanide (KCN) and verapamil were shown to increase the levels of VM-26 in LIa5 microM but not L1210 cells. These agents also selectively increased the formation of breaks in the DNA of LIa5 microM but not L1210 cells. The DNA unknotting assay with phage P4 DNA indicated equivalent DNA type II topoisomerase activity in nuclear extracts of LIa5 microM and L1210 cells. The factor that reduced the formation of breaks in cellular LIa5 microM DNA by VM-26 provided less protection against equitoxic levels of doxorubicin, to which LIa5 microM cells are cross-resistant.

Melanin synthesis and the action of L-dopa and 3,4-dihydroxybenzylamine in human melanoma cells.

The toxicity and selectivity of 3,4-dihydroxybenzylamine (DHBA), an experimental antimelanoma agent that cannot enter the melanin pathway, broadly paralleled that of L-dopa in a panel of human melanoma cell lines sensitive or resistant to the latter drug. A human retinoblastoma cell line was found to be sensitive to both compounds. The toxicity and selectivity of both catechols were associated with inhibition of DNA synthesis; DHBA was more potent yet allowed a much greater degree of recovery compared with an equitoxic level of dopa. Dopa and DHBA had similar, dose-dependent effects on the cell cycle, arresting cells in S phase at low doses and in G1 at high doses. Replication of the DNA virus adenovirus was found to be inhibited by both agents. There was no difference between sensitive and resistant cell lines in the manganese or copper/zinc forms of superoxide dismutase, or in iron content and iron-binding capacity. Catechol toxicity was inhibited by the hydrogen peroxide scavenging agents pyruvate and methaemoglobin. Sensitivity to catechols did not correlate with melanin or tyrosinase content, rate of incorporation of tyrosine or dopa, intracellular levels of phenylalanine or tyrosine, or binding of a new monoclonal antibody directed against a melanosomal protein. These results indicate that DHBA and dopa exhibit selective toxicity for neural crest tumor cells independently of the melanisation pathway and of the superoxide scavenging system.

Acute toxicity of organic chemical mixtures to the fathead minnow

The acute joint toxicity of industrial organic chemicals to the fathead minnow was determined for binary and equitoxic multiple chemical mixtures. Results from binary tests were used to define isobole diagrams. The degree of joint toxic action was determined among 27 chemicals from seven different chemical classes. The slopes of the acute concentration response relationships were quite similar for all test chemicals. This suggests that the mode of acute toxic action for these chemicals is alike though it may not be identical. Intoxication signs of fish exposed to nearly all test chemicals were also similar and indicative of an anesthetic like effect. The results of isobole diagrams for binary mixtures, with 1-octanol as the reference chemical, demonstrated a near concentration additive acute joint action over a wide range of mixture ratios for each chemical from 7 different classes. Tests conducted with mixtures containing equitoxic levels of two to 21 chemicals also displayed a concentration additive acute joint action. All test chemicals can be modeled by a structure-toxicity relationship characteristic of a narcosis type of toxic action. These results are consistent with those of other investigators and are of particular importance when one realizes that numerous industrial chemicals are likely to cause lethality to aquatic organisms through similar toxic action.

Effects of sorbic acid and its salts on chromosome aberrations, sister chromatid exchanges and gene mutations in cultured chinese hamster cells

The ability of sorbic acid and its potassium and sodium salts to induce chromosome aberrations, sister chromatid exchanges (SCE) and gene mutations in cultured Chinese hamster V79 cells was examined. Sodium sorbate caused significant induction of chromosome aberrations and SCE, and also induced 6-thioguanine-resistant mutations in a dose-dependent manner. The clastogenic potency of sodium sorbate was found to be less than one hundredth of that of the potent clastogen N-methyl- N′-nitro- N-nitrosoguanidine. The induction of SCE by sodium sorbate was twice the control level, whereas that by methyl methanesulphonate, a potent inducer of SCE, was 14 times the control level. The mutagenic potency of sodium sorbate was less than one-tenth that of ethyl methanesulphonate, a potent inducer of mutation, when compared at an equitoxic level. Sorbic acid and its potassium salt induced chromosome aberrations, but only at the highest doses tested. These compounds also induced 1.2 times the control level of SCE, but neither compound induced 6-thioguanine-resistant mutations. The cytogenetic activity of sodium sorbate was concluded not to be due to the effect of osmotic pressure or an impurity. These results indicate that sodium sorbate is a genotoxic agent, although its potency seems to be weak, and that sorbic acid and potassium sorbate are less genotoxic than the sodium salt.