Discernible Toxicity Research Articles

Toxicity associated with boronophenylalanine and cranial neutron irradiation

AbstractBoron neutron capture therapy (BNCT) involves administration of a tumor selective boron compound followed by neutron irradiation directed at the target organ. Several studies have shown antitumor activity in animal models with BNCT using the amino acid analog boronophenylalanine (BPA). This study investigates the pharmacological toxicity of BPA in rabbits and the acute (14 days) and subacute (100 days) radiotoxicity of cranial BNCT with BPA in normal mice. To assess the toxicity of BPA alone the drug was administered orally in either a single dose of 5,000 mg/kg or 5 divided doses of 1,000 mg/kg/day to rabbits which were subsequently sacrificed at 2.5 or 4.5 weeks. To study the radiotoxic effects of BNCT mice were given BPA orally followed by cranial irradiation with a thermal neutron beam 3 hr later, with resulting brain doses ranging from 1,100 to 2,750 cGy‐Eq [compound‐relative biological effectiveness (C‐RBE) of 1.3 for 10B, 3.2 for neutrons, and 1.0 for gammas]. Mice were sacrificed 14 or 100 days after irradiation to study acute and subacute radiation toxicity, respectively. BPA alone demonstrated no discernible toxicity at the doses and schedules administered. BNCT resulted in a dose‐independent acute dilatation of the cerebral ventricles and mild cerebral atrophy. No neurologic deterioration could be detected in animals exposed to 2,200 cGy‐Eq or lower but acute clinical morbidity was evident at 2,750 cGy‐Eq, possibly related to non‐neural toxicity. Mice exposed to a dose of 2,750 cGy‐Eq to the brain also presented with moderately severe gastrointestinal toxicity consisting of epithelial hyperplasia or atrophy and necrosis. Animals exposed to lower doses showed no significant gastrointestinal radiotoxicity. All animals sacrificed at 100 days that received 2,200 cGy‐Eq developed bilateral posterior subcapsular cataracts. Lower doses had a minimal ocular toxic effect. It is concluded that there was no discernible toxicity from BPA administration at daily doses 10 times higher than those required for proposed therapeutic applications. Single‐fraction BNCT irradiations to the head showed significant ocular toxicity with a threshold between 1,650 and 2,200 cGy‐Eq; gastrointestinal toxicity with a threshold between 2,200 and 2,750 cGy‐Eq; and neural toxicity with a threshold ≦l,100 cGy‐Eq for histopathologic lesions. © 1995 Wiley‐Liss, Inc.

Effects of natural interferon alpha, natural tumor necrosis factor alpha and their combination on human mesothelioma xenografts in nude mice.

Effects of human natural interferon alpha (nIFN) alone, human natural tumor necrosis factor alpha (nTNF) alone and their combination (OH-1) were tested on three human mesothelioma lines implanted in nude mice. Tumors were transplanted subcutaneously by trocar on treatment day -12. nIFN was given intraperitoneally (i.p.) at a dose of 2 x 10(7) or 2 x 10(8) IU kg-1 day-1, 5 days a week for 3 weeks. nTNF was given i.p. at a dose of 2 x 10(7) or 2 x 10(8) U kg-1 day-1 in the same schedule as that of nIFN. Tumor diameters were serially measured and tumor volumes were calculated. Antitumor effects were assessed by two methods: comparison of final tumor volumes in treated and control groups (T/C), and changes in median average total tumor volume. The treatment produced no clinically discernible toxicities. nIFN had strong inhibitory activity against all three human mesothelioma lines. nTNF alone had modest activity only at the high dose used. The combination of the two produced activity essentially similar to that produced by nIFN alone. High-dose nIFN may have a role as an active agent in the treatment of patients with mesothelioma.

Developmental toxicity of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T): I. Multireplicated dose-response studies in four inbred strains and one outbred stock of mice

A large-scaled multireplicated developmental toxicity study was conducted in various strains/stocks of mice with the herbicide, 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), by gavage on Gestational Days 6 through 14. The most important attributes of the study design were replicated test groups, a minimum of four dose levels per replicate, use of multiple stocks/strains of animals to obtain an estimate of the range in sensitivities due to genotype, complete pathological evaluation of maternal animals, and histopathological as well as teratological evaluation of the fetuses. Developmental toxicity was observed at doses below those producing discernible or measurable maternal toxicity. Regression and/or probit analyses were conducted to determine whether a dose-response relationship existed. Reduced fetal weight and increased incidence of cleft palate and embryolethality were the most significant prenatal effects of 2,4,5-T exposure observed in this study. Each strain/stock exhibited a dose-related decrease in fetal weight with the CD-1 mice having the steepest slope and the A J mice having the shallowest slope. There was a striking similarity among the slopes of the dose-response curves for the various strains/stocks. The mean incidence of embryolethality in the A J strain was significantly greater than that of the other strains or stocks. There was substantial variation among replicates within strains. The use of the replicated study design was logistically necessary due to the magnitude of the study and it also served to increase the statistical power of the study.

Teratogenic effect of calcium edetate (CaEDTA) in rats and the protective effect of zinc

The calcium chelate of EDTA (CaEDTA) currently is the drug of choice in the treatment of lead intoxication. This study investigated the teratogenic potential of CaEDTA, administered parenterally during periods of organogenesis and determined if incorporating zinc into EDTA would protect against teratogenic effects. Four doses (2, 4, 6, and 8 mmol/m 2/day) of CaEDTA, two concentrations (8 and 20 mmol/m 2/day) of ZnEDTA and ZnCaEDTA (molar ratio 0.5:0.5:1) were used, and a saline control (0.9% NaCl). Timed-pregnant Long-Evans rats were assigned at random to the treatment groups, 20 per dose for each chelate and 30 to the saline control. Rats were injected with the chelate or saline solution sc, twice daily during the 11th through 15th days of gestation. Pups removed by cesarean section on the 21st day were processed for osseous and visceral examination. Additional animals per treatment group were used for maternal plasma and liver and fetal zinc determinations. Results showed increases in several abnormalities (submucous cleft, cleft palate, adactyly-syndactyly, curly tail, abnormal rib and vertebrae) with increasing amounts of CaEDTA. No malformations were seen with ZnEDTA at either dose or with ZnCaEDTA at 8 mmol/m 2/day. However, submucous cleft was seen in 6 of 20 litters from the dams receiving the higher dose of ZnCaEDTA. It was concluded that CaEDTA is teratogenic in rats at concentrations which, except for decreased weight gain, produce no discernible toxicity to the dam, and which are comparable to the recommended therapeutic dosage in humans (1500 mg/m 2/day corresponding to 4 mmol/m 2/day). Protection is afforded by incorporating zinc in the chelate.

Subchronic Toxicity Study of 1,2,4-Trichlorobenzene in the Rat, Rabbit and Beagle Dog

Male rats, rabbits and dogs were exposed to 0, 30 or 100 ppm of 1,2,4-trichlorobenzene (TCB) for 7 hours/day, 5 day/week for 30 exposures in 44 days. In all 3 species, there were no significant effects on body weight gain, hematologic and serum biochemical tests or gross and histopathologic appearance of tissues. At 100 ppm TCB, both rats and dogs had increased liver weights, and the rats also had increased relative kidney weight at this higher exposure level. Urinary excretion of porphyrins were increased in rats exposed to 30 or 100 ppm TCB, most likely as a result of hepatic induction by TCB. In view of the reversibility of this porphyrin induction noted in a companion study, and the absence of other indications of discernible toxicity, this increased urinary excretion of porphyrins is best considered more of a compound-specific physiologic effect rather than a toxic effect.

Pluronic F-68: A promising new skin wound cleanser

Pluronic F-68 is a new skin cleanser that has been approved by the Food and Drug Administration for use in humans. In experimental studies, this nonionic detergent prevented the development of infection with no discernible toxicity. We have used Pluronic F-68 clinically in wounds in more than 1,000 patients without demonstrable side effects. As a result of this experience, Pluronic F-68 has replaced all other commercially available scrub solutions for use as a skin wound cleanser in our medical center.

Diabetes in General Practice

Curcumin (diferuloylmethane), which has no discernible toxicity, inhibits initiation, promotion and progression of carcinogenesis. 5-Fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX) remains the backbone of colorectal cancer chemotherapeutics, but produces an incomplete response resulting in survival of cells (chemo-surviving cells) that may lead to cancer recurrence. The present investigation was, therefore, undertaken to examine whether addition of curcumin to FOLFOX is a superior therapeutic strategy for chemo-surviving cells. Forty-eight-hour treatment of colon cancer HCT-116 and HT-29 cells with FOLFOX resulted in 60-70% survival, accompanied by a marked activation of insulin like growth factor-1 receptor (IGF-1R) and minor to moderate increase in epidermal growth factor receptor (EGFR), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (HER-2) as well as v-akt murine thymoma viral oncogene homolog 1 (AKT), cyclooxygenase-2 (COX-2) and cyclin-D1. However, inclusion of curcumin to continued FOLFOX treatment for another 48 h greatly reduced the survival of these cells, accompanied by a concomitant reduction in activation of EGFR, HER-2, IGF-1R and AKT, as well as expression of COX-2 and cyclin-D1. More importantly, EGFR tyrosine kinase inhibitor gefitinib or attenuation of IGF-1R expression by the corresponding si-RNA caused a 30-60% growth inhibition of chemo-surviving HCT-116 cells. However, curcumin alone was found to be more effective than both gefitinib and IGF-1R si-RNA mediated growth inhibition of chemo-surviving HCT-116 cells and addition of FOLFOX to curcumin did not increase the growth inhibitory effect of curcumin. Our data suggest that inclusion of curcumin in conventional chemotherapeutic regimens could be an effective strategy to prevent the emergence of chemoresistant colon cancer cells.