Re-Examination of the Esophageal Squamous Cell Carcinoma Model in Rats Induced by N-Nitrososarcosine Ethyl Ester Precursors.

Studies of the molecular mechanisms of esophageal cancer development have to be carried out on sufficient amount of tumor material, obtained under conditions of controlled exposure to carcinogenic factors. Esophageal cancer models on laboratory animals serve an indispensable source of this material. One of these models is esophageal cancer induction in rats by N-nitroso compound precursors. Despite adequate reproduction of human esophageal cancer, this model in fact has not been used since the 1990ies. Re-examination of esophageal cancer model, induced by N-nitrososarcosine ethyl ester precursors, is carried out and its efficiency in induction of squamous cell carcinoma is confirmed.

[Inhibitory effect of human lactoferrin (neolactoferrin) on the growth of transplantable tumor in the uterine cervix of mice].

There was studied effect of recombinant form of human breast milk component-lactoferrin, received from milk of goats-producers (neolactoferrin), on growth of transplantable tumor of the cervix in mice (TTC-5). Neolactoferrin in dose of 100 mg/kg and 200 mg/kg of animals' mass inhibited the rate of tumor growth. The most effective was the dose of 200 mg/kg, which was entered a week before transplantation. In contrast to the control group, in groups where neolactoferrin was entered it was fixed resorption of TTC-5 in 6 mice. Repeated transplantation TTC-5 to these mice led to reducing of the rate of tumor growth and increasing of duration of their lives. To investigate if tumor-braking effect neolactoferrin connected with direct effect on the tumor or due to the general effect of the organism, TTC-5 cells were transformed in culture and they were exposed by neolactoferrin in dose of 10 and 100 mkg/ml. In investigated doses neolactoferrin did not influence on tumor cells growth. There is discussed possible mechanism of anti-tumor effect of neolactoferrin.

[Influence of dichlorodiphenyldichloroethylene on 1,2 dimethylhydrazine-induced androgen-dependent renal capsule angiosarcoma development].

The study was concerned with the influence of dichlorodiphenyldichloroethylene (p,p'-DDE) on 1,2 dimethylhydrazine (DMH)-induced androgen-dependent renal capsule angiosarcoma (RCA) in male CBA mice. p,p'-DDE was shown to significantly decrease the incidence of DMH-induced RCA (69.0% vs. 44.1%). That could be accounted for by the anti-androgen affinity of p,p'-DDE. It is suggested that exposure to p,p'-DDE might inhibit androgen-receptor containing tumors.

[Low-deuterium water effect on transplantable tumors].

Such models of transplantable tumors as Lewis sarcoma, uterine sarcoma-322 and uterine carcinoma-5 were used to study possible inhibitory effect by low-deuterium water. Such water was given to experimental animals (20 mice in each group). Controls (30 in each group) received tap water with standard deuterium concentrations. Low-deuterium water treatment resulted in significant inhibitory effect on volume of all tumor patterns concerned: it delayed nodule formation at transplantation site. However, no increase in survival time was obtained.

[Diethylstilbestrol-induced uterine sarcoma in mice]. / Sarkomy matki myshei, indutsirovannye diétilstil'béstrolom.

Female mice of CBA strain received diethylstilbestrol (DES) 1 g body weight intraperitoneally. High incidence of histiocytic uterine sarcoma was observed in parents (25%), first generation (F1), descendants (10.9%), and generation F2m (through F1 males mated with females in control) (17.8%). Morphologically, tumor cells examined through light and electron microscopy were referred to as histiocyte-like elements. Half of the animals had metastases in the liver, kidneys, lungs, spleen, pineal and adrenal glands and stomach. The development of tumors in generation F2m, which was not exposed to DES, might be accounted for by "transgeneration" carcinogenesis, i.e. passage of carcinogenic effect through a generation.

[N-nitrosodiethylamine-induced changes in the liver of syrian hamster with superinvasive opistorchiasis]. / Izmeneniia v pecheni khomiachkov, indutsirovannye n-nitrozodiétilaminom pri superinvasionnom opistorkhoze.

Trematoda O. felinius-induced hepatic lesions were investigated in Syrian golden hamsters with superinvasive opistorchiasis. One hundred hamsters were divided into 4 groups: (1)--control; (2) N-nitrosodiethylamine (DENA), i.p., twice a week, 3 weeks, total dose 72 mg/kg; (3) metacercariae O. felinius, with drinking water, 3 injections per day, once in 2 weeks, and (4) metacercariae O. felinius, as in group 3, followed by DENA, as in group 2. Animals were sacrificed 12 months after the beginning of the study. No changes in the liver were found in group 2. Reddish protrusions, up to 4 cm in diameter, appeared on liver surfaces in groups 3 and 4. Group 4 featured the highest relative and absolute weights of liver as well as clusters of oval cells and cholangiocellular tubules and cholangiofibrosis (in group 3, they were less visible). Electron microscopic examination identified hepatocytes with destructive changes to plasmalemma, nucleus and cytoplasmic organelles. Also, perisinusoidal cells (Ito cells) occurred. Tumor-bearing animals showed low hepatic cytochrome P-450. It is suggested that proliferative growth in the liver was stimulated by opistorchis invasion.

[Consideration of the deuterium-free water supply to an expedition to Mars]. / Vozmozhnost' ispol'zovaniia bezdeiterievoi vosy v marsianskoi ékspeditsii.

Interplanetary missions, including to Mars, will put crews into severe radiation conditions. Search for methods of reducing the risk of radiation-induced cancer is of the top priority in preparation for the mission to Mars. One of the options is designing life support systems that will generate water with low content of the stable hydrogen isotope (deuterium) to be consumed by crewmembers. Preliminary investigations have shown that a decrease of the deuterium fraction by 65% does impart to water certain anti-cancer properties. Therefore, drinking deuterium-free water has the potential to reduce the risk of cancer consequent to the extreme radiation exposure of the Martian crew.

1,2-Dimethylhydrazine carcinogenesis in CBA male mice prenatally treated with diethylstilbestrol.

CBA female mice, at the 17th day of pregnancy, received single intraperitoneal injection of diethylstilbestrol (DES) at the dose of 1 mg/kg body weight (b. w.). Their descentands at the age of 2 months started receiving subcutaneous injections of 1,2-dimethylhydrazine (DMH) at the dose level of 8 mg(base)/kg b. w., total 15 weekly injections. Prenatal DES treatment of male mice considerably accelerated the development and increased the incidence of DMH-induced androgen-dependent renal adenomas and, notably, renal capsule angiosarcomas (RCA). In males receiving prenatal DES (without subsequent DMH-treatment), there was a statistically significant increase of renal adenomas and 9% of RCA were observed which are exceedinly rare in untreated mice. The enhancement of androgen-dependent tumourigenesis may be considered as an indication, even though indirect, of the hyperandrogenization produced in male mice by the prenatal DES treatment.

[Effect of prenatal treatment with diethylstilbestrol on 1,2-dimethylhydrazine-induced carcinogenesis in male CBA mice]. / Vliianie prenatal'nogo vozdeistviia diétilstil'béstrola na katserogenez, indutsiruemyi 1,2-dimetilgidrazinom u myshei-samtsov linii CBA.

Female CBA mice were injected 1 mg/kg diethylstilbestrol (DES) on day 17 of gestation. Their male progeny received 15 weekly injections of 1,2-dimethylhydrazine (DMH) starting from the age of 2 months. Prenatal treatment with DES was followed by a significant acceleration and higher frequency of DMH-induced renal adenomas and renal capsule sarcomas in males. Tumor-induction was significantly enhanced by androgen effect. This was matched by a higher frequency of induced tumors of the large bowel. The increased frequency of androgen-dependent renal malignancies, served as indirect evidence of hyperandrogenization being stimulated in CBA male mice by prenatal treatment with DES.

Predominant p53 G-->A transition mutation and enhanced cell proliferation in uterine sarcomas of CBA mice treated with 1,2-dimethylhydrazine.

Mouse uterine tumors were examined for genetic alterations in the ras proto-oncogene and p53 tumor suppressor gene and for other biologically relevant immunohistochemical markers that may increase our understanding of the events that occur in uterine cancer. Fourteen dimethylhydrazine (DMH)-induced uterine sarcomas, including 3 primary malignant fibrous histiocytomas (MFH), 7 transplanted MFH, 3 stromal sarcomas, and 1 undifferentiated sarcoma, were first screened by immunohistochemistry for p53 missense mutations, followed by single strand conformation polymorphism analysis and DNA sequencing for the identification of point mutations. There was 100% correlation between p53 protein immunopositivity and subsequent detection of p53 mutations in DMH-induced malignant fibrous histiocytomas. All MFH had a characteristic p53 G:C-->A:T transition mutation, consistent with O6-methylguanine mispairing with thymine, the most common DNA lesion caused by alkylating agents. DMH-induced uterine MFH with p53 mutations also had a higher proliferative rate (qualitatively evaluated by immunohistochemical detection of proliferating cell nuclear antigen) when compared with other DMH-induced sarcomas. Uterine sarcomas were further evaluated for biological end points, such as estrogen receptor and desmin. Neoplastic cells from stromal sarcomas (SS), undifferentiated sarcomas (US), and MFH did not stain for desmin. The estrogen receptor was detected in normal uteri and a small portion of MFH, SS, and US. Our data suggest that DMH-induced uterine sarcomas are not consistent with smooth muscle cell origin and that a subset of these tumors, specifically DMH-induced malignant fibrous histiocytomas, have unique p53 G:C-->A:T transitions and a high proliferative rate.

1,2-Dimethylhydrazine carcinogenesis in C3HA and CBA female mice prenatally treated with diethylstilbestrol.

C3HA and CBA female mice received a single intraperitoneal (i.p.) injection of 0.1 or 0.3 mg/kg body weight (b.w.) of diethylstilbestrol (DES) at day 17 of pregnancy. The descendants, starting from the age of 2-3 months, were receiving weekly subcutaneous (s.c.) injections of 1,2-dimethylhydrazine (DMH) (8 mg/kg b.w.), total 20 injections. The survival of C3HA mice treated with DMH together with prenatal DES was considerably better than in mice treated with DMH alone, this being due to the strong inhibiting effect of DES on the induction by DMH of the hemorrhagic ovarian lesions (78.4% in DMH alone vs. 53.3 and 43.7% in groups with DES plus DMH), which frequently were the cause of animal death. Prenatal DES also inhibited the induction by DMH of clitoral gland tumors: 51.4% in the group with DMH alone vs. 26.6 and 28.1% in two groups of DES plus DMH, respectively. DES treatment, at the above doses, did not influence significantly the DMH carcinogenesis in CBA mice. Prenatal DES given to CBA mice at the dose of 1 mg/kg b.w. significantly increased the incidence of DMH-induced uterine sarcomas (42.8% vs. 73.3% in the group with DMH alone and the group receiving DMH together with prenatal DES, respectively) and accelerated their growth. The effects of prenatal DES on DMH-induced carcinogenesis correlated with the degree of hyperestrogenization produced in both strains of mice by DES.

Sarcomatous lesions in CBA female mice treated with 1,2-dimethylhydrazine: independent primaries or metastases?

CBA female mice treated with 1,2-dimethylhydrazine (DMH) alone or in combination with oestradiol dipropionate (EP) or ascorbic acid (AA) developed, as expected, a high incidence of uterine sarcomas. In addition, sarcomatous lesions at unusual sites (mainly in the forestomach) were evident. The incidence of sarcomatous lesions at other sites was 53/220 in mice having uterine sarcomas and 0/186 in mice treated with DMH but without uterine sarcomas. The difference between the two groups was highly statistically significant (P < 0.001) and demonstrates non-coincidental association of the above sarcomatous lesions with uterine sarcomas. Uterine sarcomas which presented in association with lesions at other sites were of a larger size than those found in isolation, and the difference in weights in three out of four groups was statistically significant (P = 0.008, 0.035 and 0.011). Histologically, sarcomatous lesions were similar in structure to those of uterine sarcomas, i.e. were of a fibroblastic-histiocytic nature with admixture of giant cells. On the basis of the above data the sarcomatous lesions described appear to represent uterine sarcoma metastases rather than independent primary tumours. AA did not have any influence on carcinogenesis induced by DMH alone but inhibited the growth of uterine sarcomas (whether or not they were associated with other sarcomatous lesions) induced by DMH combined with oestradiol dipropionate.

Uterine sarcomas in CBA mice induced by combined treatment with 1,2-dimethylhydrazine and estradiol dipropionate. Light and electron microscopy.

Three uterine sarcomas induced by combined treatment (1,2-dimethylhydrazine and estradiol dipropionate) in CBA mice were examined by light and electron microscopy. Histologically the tumours consisted either of loose areas with stellate cells or of solid cellular areas. These were formed of elongated cells of the fibroblastic type and rounded cells with clear nuclei and abundant cytoplasm without clearly discernible bodies. Ultrastructurally, undifferentiated mesenchymal cells and cells with the features of fibroblasts and myofibroblasts were distinguished. The tumours described bear resemblance to human endometrial stromal sarcomas and are interpreted as sarcomas originating from immature mesenchymal cells differentiating mainly in the direction of cells of the fibroblastic type. Certain similarities with fibrous histiocytomas are noted.

Occurrence of tumours in the descendants of CBA male mice prenatally treated with diethylstilbestrol.

There is well documented evidence both in humans and in experimental animals that exposure to diethylstilbestrol (DES) during pregnancy results in an increased incidence of tumours in the progeny. The increased cancer risk has been reported to persist in the second generation descendants of DES-exposed pregnant mice. In the present experiment, female mice of the CBA strain were treated at day 17 of pregnancy with 1 microgram/g body weight of DES. The descendants of DES-treated mothers, described as F1DES, were mated among each other or with untreated animals. The F1DES females were found to be sterile when mated with either F1DES or untreated males. F1DES males were successfully mated with untreated females. In the female offspring so obtained, but not in the male, a statistically significant increased incidence of tumours was observed, in particular of uterine sarcomas, and also of benign ovarian tumours and of lymphomas.

Modifying effect of ascorbic acid and sodium ascorbate on the promoting stage of uterine sarcomogenesis induced in CBA mice by 1,2-dimethylhydrazine and estradiol-dipropionate.

Administration of estradiol-dipropionate (EP) after the cessation of 1,2-dimethylhydrazine (DMH) treatment increased the incidence of uterine sarcomas in CBA mice from 32.5 (DMH alone) to 62.5%. Ascorbic acid (AA) (0.3% in drinking water) given simultaneously with EP decreased the tumour incidence to 35%. Sodium ascorbate did not exert an inhibiting effect. AA inhibited the increase of uterine weight produced in mice by EP and did not influence the growth of mouse transplantable uterine sarcomas. The mechanisms of the antiestrogenic effects of AA are discussed.

[The inhibitory effect of ascorbic acid on the estrogen-stimulated promotion of uterine sarcoma development in mice]. / Tormoziashchii éffekt askorbinovoi kisloty na stimulirovannuiu éstrogenom promotsiiu sarkomogeneza matki u myshei.

The administration of estradiol propionate after the discontinuation of 1,2-dimethylhydrazine (DMH) treatment increased the incidence of uterine sarcoma in CBA mice from 32.5 (DMH alone) to 62.5%. The addition of the ascorbic acid (0.3% solution in drinking water) to estradiol propionate was followed by a decrease in the tumor incidence to 35%, i. e. the acid levelled the promoting effect of estradiol propionate almost completely. Sodium ascorbate did not share that effect. Mechanisms underlying the antiestrogenic effect of the ascorbic acid are discussed.

[Effect of estradiol dipropionate on the development of uterine sarcoma induced by 1,2-dimethylhydrazine in mice]. / Vliianie éstradiola dipropionata na razvitie sarkom matki, vyzyvaemykh 1,2-dimetilgidrazinom u myshei.

The study was concerned with the influence of single dose of estradiol dipropionate on its promoting effect on 1,2-dimethylhydrazine-induced tumors in female CBA/CaLac mice. Estradiol dipropionate given within 19 weeks did not affect carcinogenesis whereas 39-week treatment stimulated uterine sarcoma development irrespective of single dose and schedule of administration.

[Modifying effect of ascorbic acid and sodium ascorbate on uterine carcomogenesis induced by 1,2-dimethylhydrazine in CBA mice]. / Modifitsiruiushchee vliianie askorbinovoi kisloty i askorbata natriia na sarkomogenez matki u myshei linii CBA, indutsirovannyi 1,2-dimetilgidrazinom.

Administration of ascorbic acid (0.3% in drinking water) inhibited the promoting effect of estradiol dipropionate on the 1,2-dimethylhydrazine-induced uterine sarcomogenesis in CBA mice. However administration of sodium ascorbate intensified the promoting effect of estradiol on the uterine sarcomogenesis, as evidenced by the shortening of the periods of tumour incidence.