Nonclinical reproductive and developmental safety evaluation of the MAGE-A3 Cancer Immunotherapeutic, a therapeutic vaccine for cancer treatment.

We assessed potential toxic effects of the MAGE-A3 Cancer Immunotherapeutic on female fertility and embryo-fetal, pre- and post-natal development in rats and on male fertility in rats and monkeys. Three groups of 48 female (Study 1) or 22 male (Study 2) CD rats received 5 or 3 injections of 100µL of saline, AS15 immunostimulant, or MAGE-A3 Cancer Immunotherapeutic (MAGE-A3 recombinant protein combined with AS15) at various timepoints pre- or post-mating. Male Cynomolgus monkeys (Study 3) received 8 injections of 500µL of saline (n=2) or the MAGE-A3 Cancer Immunotherapeutic (n=6) every 2 weeks. Rats were sacrificed on gestation day 20 or lactation day 25 (Study 1) or 9 weeks after first injection (Study 2) and monkeys, 3 days or 8 weeks after last injection. Injections were well tolerated. Female rat mating performance or fertility, pre- and post-natal survival, offspring development up to 25 days of age, and male mating performance (rats) or fertility parameters (rats and monkeys) were unaffected.

Sucralose: assessment of teratogenic potential in the rat and the rabbit.

The teratogenic potential of sucralose was examined following gavage administration to pregnant rats and rabbits during organogenesis. Groups of 20 mated rats were dosed on days 6-15 of gestation inclusive at 500, 1000 or 2000mg/kg/day; groups of 16 to 18 inseminated rabbits were dosed on days 6 to 19 of gestation inclusive at 175, 350 or 700mg/kg/day following preliminary studies at higher doses. Concurrent control groups received vehicle alone. Rats were killed on day 21 and rabbits on day 29 of gestation. Foetuses were evaluated at necropsy and after processing for possible soft tissue and skeletal alterations. There was no evidence of teratogenicity for either species. The only observed response to treatment in rats was a slight increase in water intake. Some adult rabbits receiving 700mg/kg/day exhibited marked gastrointestinal disturbance, also seen at higher doses in preliminary studies. Gastrointestinal effects such as these occur non-specifically in response to high doses of poorly absorbed compounds, and in the present study were considered to be responsible for two maternal deaths and four abortions. Full evaluation of rabbit foetuses in the main study (up to 700mg/kg/day) and necropsy of foetuses in a preliminary study with pregnant animals (up to 1000mg/kg/day) showed no evidence of adverse foetal response to sucralose. These teratology studies in both pregnant rodent and non-rodent animal models demonstrate that maternal consumption of high levels of sucralose during the period of organogenesis has no effect on normal foetal development in the rat or rabbit.

Assessment of the toxic and potential teratogenic effects of four glycol ethers and two derivatives using the hydra regeneration assay and rat whole embryo culture.

The widespread use of the glycol ethers as solvents in manufacturing industries presents a vast potential for occupational exposure. In the present study the potential hazards of four glycol ethers and two derivatives were assessed using two in vitro tests, rat whole embryo culture and the hydra regeneration assay. Concentrations used ranged from 0.3 to 1.0 mg/ml in embryo culture and from 0.03 to 80.0 mg/ml in the hydra assay. The embryotoxic potential of the ethylene glycol mono-alkyl ethers was shown to increase with the length of the alkyl chain. This is in contrast to in vivo data but can be explained by the lack of maternal metabolism in the in vitro systems. However, the teratogenic hazard ratings obtained in the hydra assay and the types of malformations observed in embryo culture support in vivo data. Results obtained for diethylene glycol monoethyl ether are in agreement with in vivo data. Results of both assays suggest that ethylene glycol monosalicylate presents a significant potential teratogenic hazard and that ethylene glycol tetra-acetic acid presents toxic and teratogenic potentials. When the effects of maternal toxicity and metabolism are considered, the overall picture presented by the present results is one of general agreement with in vivo data.

[Reproductive and developmental toxicity studies of lactitol (NS-4) (3)--Teratogenicity study in rabbits by oral administration].

Lactitol, a hepatic encephalopathy drug, was administered by oral gavage to pregnant New Zealand White rabbits during organogenesis from day 6 to day 18 of gestation inclusive, at dosages of 0, 0.25, 0.75 or 4.5 g/kg/day. On day 29 of gestation, females were killed to allow examination of their uterine contents. There was a slight reduction in food intake and faecal output among females receiving 4.5 g/kg. One female receiving 4.5 g/kg aborted following a prolonged period of weight loss. No adverse effects on litter parameters were recorded that could be attributed to treatment. Foetal morphogenesis was unaffected by treatment with lactitol. The results show that no-effect dose levels of lactitol are 0.75 g/kg in mother rabbits for general toxicity and for reproductive functions, and 4.5 g/kg for their fetuses.

Reproductive studies of NY-198 in rats. I. Fertility study.

Lomefloxacin (NY-198), a new antibacterial agent, was administered daily by gavage to groups of 22 male and 22 female rats at dosages of 30, 100 or 300 mg/kg/day. Males were dosed for 71 days before pairing and then until termination, and females were dosed for 15 days before pairing, throughout mating and until Day 7 of gestation. Females were killed on Day 20 of gestation for examination of their uterine contents. Males were killed after approximately 14 weeks treatment and their reproductive organs were weighed and retained. At 300 mg/kg/day the majority of animals showed increased salivation, water intake was slightly increased throughout the treatment period in males and before pairing in females whereas food intake showed a slight, transient reduction during the first few days of treatment in both sexes. Body weight gain of males was marginally depressed during the first week of treatment, but no other signs of reaction to treatment were observed. At 30 and 100 mg/kg/day some animals exhibited increased salivation after being dosed. At all dosages, NY-198 was without adverse effects upon mating performance and fertility, or upon survival, growth and development in utero. On the basis of the above results it is considered that the no effect level with respect to reproduction and breeding performance of treated F0 animals and the in utero development of the foetuses was 300 mg/kg/day. A dosage of 100 mg/kg/day was considered to be the no effect level for somatic changes in the F0 animals, and even at the highest dosage of 300 mg/kg/day only slight effects were recorded on the F0 animals.

Reproductive studies of NY-198 in rats. II. Teratology study.

Lomefloxacin (NY-198), a new antibacterial agent, was administered daily by gavage to groups of 32 pregnant female rats of the CD strain at dosages of 30, 100 or 300 mg/kg/day from Day 7 to Day 17 of gestation. Twenty-one females in each group were killed on Day 20 of gestation for examination of their uterine contents. Eleven females in each group were allowed to deliver their litters and the offspring were examined for growth and functional development. At the highest dosage (300 mg/kg/day), there was a small reduction in maternal weight gain and a transient reduction in food intake during the treatment period. Foetal and placental weights were markedly reduced. However, survival, growth and development of F1 offspring were unaffected and, with the possible exception of a slight reduction in F2 foetal weight, their reproductive performance was unimpaired. At the intermediate level (100 mg/kg/day), maternal body weight gain and food intake during the treatment period were slightly reduced but, with this exception, the performance of F0 females and of the F1 generation was essentially similar to that of the vehicle controls. At the lowest dosage (30 mg/kg/day), no adverse effects were recorded on either the F0 females or the F1 generation. On the basis of the above results 30 mg/kg/day was considered to be the no effect level for the F0 females treated during gestation while 100 mg/kg/day administered during gestation to F0 females had no effect upon performance of the F1 generation.

Reproductive studies of NY-198 in rats. III. Perinatal and postnatal study.

Lomefloxacin (NY-198), a new antibacterial agent, was administered daily by gavage to groups of 22 pregnant female rats of the CD strain at dosages of 30, 100 or 300 mg/kg/day from Day 17 of gestation to Day 21 of lactation. Females were allowed to deliver their litters and the offspring were examined for growth and functional development. There was a slight maternal response at the highest dosage (300 mg/kg/day), including increased salivation after dosing, reduced food intake in the treated period of gestation and increased water intake during the lactation period. Gestation length was slightly increased, although remaining within the laboratory background control range; in consequence, body weight of F1 offspring at Day 1 post partum was slightly increased. At 100 mg/kg/day, a few females showed increased salivation after dosing and there was a slight increase in gestation length. Birth weight of F1 offspring was slightly increased at 30 and 100 mg/kg/day but all values were within laboratory background control ranges. The survival, functional responses and fertility of F1 offspring were essentially unaffected by NY-198. On the basis of the above results, 30 mg/kg/day was considered to be the no-effect level for the F0 females treated during late gestation and lactation whilst 300 mg/kg/day administered to the F0 females had no adverse effect upon their offspring.

Golgi orientation and cell behaviour in the developing pattern of chondrogenic condensations in chick limb-bud mesenchyme.

Using a silver-impregnation method, the occurrence and significance of Golgi apparatus orientation has been studied in cells contributing to the cartilage condensations in the developing skeleton of the chick limb bud, both in normal embryos and in the talpid mutant, in which the pattern of condensation in situ, and cell behaviour in vitro, is abnormal. Analysis of photographed sections made up as photomontages with a final magnification of X 1000, indicates a sequence of changing Golgi orientation in the course of establishing cartilage condensations in the mesenchyme in normal limb buds, including at an early stage an orientation of one population of cells towards the condensation centre and of another population in the contrary direction, and a modification of the sequence in the mutant. The changing patterns of cell orientation has been further analysed in scanning electron microscope studies on the formation of cartilage condensations in vitro.

Control of somite number in normal and amputated mutant mouse embryos: an experimental and a theoretical analysis.

A regulation is shown for size and number of serially repeated axial structures, the somites, in a mammalian embryo. The mammalian embryo is normally inaccessible to operation at post-implantation stages. This problem is resolved by the quantitative analysis of somite size, number and development in a recessive mutant of the mouse, amputated, whose axial length is greatly reduced. The effect of the gene simulates an experiment ablating part of the embryonic tissue available for somitic segmentation. Regulation occurs at the time when the somite is first formed, by control of the quantity of cells included in each new somite. A model is devised for the control of somitic segmentation which explains most of the features observed and which can be simulated on a computer.