Tumor target organs and rate of survival in long-living transgenic mice and their parental wild-type counterparts exposed to the carcinogen dimethylbenz(a)anthracene.

Two-year-old mice of the long-living transgenic mice of the alphaMUPA strain were previously found to show higher tumor resistance than the their initial wild-type (WT) strain (Tirosh, 2003). To better understand the mechanism underlying the differences in tumorigenesis rates between the two mouse lines, the rate of tumorigenesis and survival effects were studied in alphaMUPA mice and parental WT mice exposed to dimethylbenz(a)anthracene (DMBA). Each animal received three intragastric feedings of DMBA, each one week apart, at doses of 2, 1, and 1 mg dissolved in 0.2 ml corn oil; thus, the total amount of the carcinogen was 4 mg/mouse. Control mice received corn oil. The alphaMUPA mice exhibited distinctly higher survival rates in experimental chemically-induced tumorigenesis compared to their WT counterparts: 93% vs. 67%, p =2.7. The rate of tumorigenesis differed between the mouse lines (yield was 1.5 and 2.1), owing to a distinct tendency toward decreased tumor frequency in the skin and forestomach in the alphaMUPA mice. The experimental duration was also significantly higher for transgenic mice: 35.9 +/- 1.2 weeks compared to 30.5 +/- 1.3 weeks in WT mice, p <0.01. The lungs, forestomach and skin were target organs for the carcinogenic effect of DMBA. Our observations suggest that aging promotes the rate of spontaneous and induced tumorigenesis.

Effect of the synthetic pineal peptide epitalon on spontaneous carcinogenesis in female C3H/He mice.

The potential preventive effect of the synthetic pineal peptide Epitalon (Ala-Glu-Asp-Gly) on spontaneous tumorigenesis in mice was studied. One-year-old female C3H/He mice were kept for 6.5 months under standard conditions. Epitalon was injected at a dose of 0.1 microg, 5 times a week. Long-term exposure to Epitalon in small doses did not show any toxic effect. Treatment with Epitalon decreased the number of tumor-bearing mice with malignant tumors and prevented the development of metastases. Spontaneous tumors of the reproductive organs (mammary glands and ovaries) were predominant in both groups of mice (control and experimental). The mammary gland tumors were different variants of invasive ductal carcinomas. In the ovaries, granulosa-cell tumors were found. Tumors were in the minority in other organs and had benign characteristics. In control mice, metastases were found in 3 out of 9 tumor-bearing mice, all of them being from tumors of the reproductive organs. Treatment with Epitalon slowed down the development of metastases from spontaneous tumors, and no metastases were found in the experimental mice. These data highlight the antimetastatic effect of Epitalon as part of its oncostatic properties.

The morphological pathway for mouse forestomach cancer.

We analyzed the morphological changes accompanying the development of cancer in the mouse forestomach. The main aim of the study was to evaluate whether cancer in this area of the stomach arises de novo or undergoes a series of precancerous changes. Tumors were induced by the 1,2-dimethylbenz(a)antracene (DMBA) at a total dose of 4 mg/mouse. The suspected areas of the stomach were studied morphologically in 79 mice. Benign tumors (squamous-cell papillomas) and malignant tumors (squamous-cell carcinomas) were found in 40 mice. Tumors arose in all cases together with differential changes in the forestomach epithelium. These changes were seen as irregular diffuse hyperplasia or focal proliferation, with or without differential signs of dysplasia. Destruction of the basal epithelial membrane indicated transformation of the process into malignant invasive carcinoma. Thus, in chemically induced cancer of the forestomach, squamous-cell carcinoma develops as the final stage of morphologically recognizable precancerous changes in the epithelial layer. De novo formation of such tumors in the forestomach was not observed.

Preventive effect of the soluble tumor-associated antigens on DMBA induced tumorigenesis in C3H/He mice.

In our previous studies, we showed that soluble tumor-associated antigens (sTAA) of 66 kDa and 51 kDa have distinct tumor-preventive effects on chemically induced mammary cancer in rats and are able to repair the damage caused by tumorigenesis in its early stages. In the present study, we investigated whether these proteins can prevent the development of chemically induced tumors in mice. The study was performed on C3H/He mice which have the ability to develop many spontaneous tumors with age. Forty-four, 6-week-old mice were exposed twice at a 2-week interval to the carcinogen 9,10-dimethyl-1,2-benz(alpha)anthracene (DMBA), at a dose of 2 mg/mouse administered intragastrically. Two months later, the mice were divided into two groups. One group received sterile saline twice a week at a dose of 0.2 ml/mouse, intraperitoneally (i.p.). The other group received sTAA twice a week at a dose of about 10 microl in 0.2 ml of sterile saline/mouse, i.p. Periodically, all mice were checked for the presence of tumors. The experiment was terminated at week 35. Vaccination with sTAA increased the time of involvement of mice in the experiment, prevented the tumorigenic effect of DMBA, and inhibited further development of existing tumors.

Effects of tamoxifen and soluble tumor-associated antigens on ovarian structure in mammary tumor-bearing rats.

Previously, we showed that the 66 and 51 kDa soluble tumor-associated antigens (sTAAs) have distinct suppressive effects on chemically induced mammary cancer in rats, both alone and in combination with the hormone-related anticancer drug tamoxifen. Here, we describe the effects of both sTAA and tamoxifen on the histological structure of ovaries in mammary tumor-bearing 30- to 34-week-old rats. Central ovary sections were pooled, the number of the healthy and degenerated follicles were counted, and the size of the corpora lutea was estimated. In follicular development primordial, primary, preantral and antral stages were recognized. Only healthy follicles with visible nuclei were counted. Follicular degeneration was estimated as the number of atretic follicles with follicular remnants. Treatment with tamoxifen alone or in combination with sTAA significantly increased the number of primordial follicles and atretic follicles in the ovaries, and promoted the formation of small follicular cysts. Total area of the corpora lutea decreased. sTAA participated in this process by increasing apoptosis in degenerated follicles.

Transport of maternal immunoglobulins through the human placental barrier in normal pregnancy and during inflammation.

We studied the effect of ascending infections of the birth canal on the transport of maternal immunoglobulins (Igs) through the placental barrier in humans. The study was performed on 41 human placentas obtained from embryos (n=21) and fetuses (n=20) who had died from different causes, including those connected with ascending infections of the birth canal, and seven placentas obtained after normal delivery at term. Different morphological and immunohistochemical methods were used. The transfer of Igs through the placental barrier is a complex process that involves tissues (trophoblast, stroma of the trophoblastic villi, and capillaries), cells (monocytes and erythroblasts) and molecular components (at least six types of transfer receptors and biologically active components). We found that the intensification of transfer of different types of maternal Igs (IgG, IgA, IgM) is accompanied by certain morphological and functional changes in the placental barrier. In normal development without infection, the transfer of IgG is steady and the process most intensive, while the transfer of IgA was evaluated in 75% of the cases, and of IgM in only 10%. Inflammation of the birth canal was accompanied by an increase in the transport of IgG in early embryogenesis, which was maintained throughout intrauterine development. In cases with moderate infection, transfer of IgG and IgA was found in all cases studied, while transfer of IgM was seen in 45% of the cases. In cases with massive infection, transfer of all three types of Igs was seen, the most intensive being of IgG and the least of IgM. Ascending infection of the birth canal changes dramatically the transport of Igs through the placenta and can be dangerous and even fatal for the embryo or fetus.

Two secretory immune systems (mucosal and barrier) in human intrauterine development, normal and pathological (Review).

The role of protein components of the secretory immune system (SIS), such as the polymeric immunoglobulin receptor/secretory component (pIgR/SC), immunoglobulins (Igs) and joining (J) chain, in human intrauterine development was reviewed. These components are already present in 3.5- to 4-week-old embryos, and found in all tissues and organs of epithelial origin. The SIS is made up of two parts: the SIS of mucous membranes and their derivatives (mucosal or secretory immune system), and the SIS of barrier structures (barrier immune system). During organogenesis, SC disappears from the cells of organs that lose their exocrine Ig-secretion function, such as the hypophysis, pancreatic islands and adrenal glands. In cells and tissues of mesenchymal origin, SC is absent from the start, i.e. during their initial development. As examples of the barrier immune system, blood-tissue and tissue-tissue barriers, such as the chorion of the placenta, the epithelium of the choroid plexuses in the brain, as well as other barrier structures to Ig transfer were considered. Besides the SC and J chain, Fc receptors, cellular and tissue structures participate in this process. Three stages were described in Ig transfer: i) passing from the maternal blood into intervillous spaces and the trophoblast, ii) shifting in the intravillous stroma and its cells, and iii) excretion into embryonic (fetal) blood through the endothelium of the trophoblastic villous capillaries. Igs of maternal origin, mainly IgG and least abundant IgA, pass through the placental barrier in healthy embryos. Following a massive antigenic attack, the increased exocrine secretion of IgG, IgA, and IgM to a lesser extent, are already seen in embryos, reflecting increased functional activity of the SIS. Thus, in human intrauterine development, the SIS is a very early immune defensive system, which presents and acts before the appearance of the common lymphoid system.

Cytological aspects of rat mammary cancer therapy with soluble tumor-associated antigens and anticancer drugs.

Some cytological aspects of rat mammary cancer therapy with soluble tumor-associated antigens (sTAA- p66 and p51) and the anticancer drug cyclophosphamide (CPA) are analyzed. Vaccination with sTAA results in a significant increase in the areas related to the production of T and B cells in the white pulp (germinal center and PALS) and in the marginal zone of the spleen. sTAA stimulate the production of CD8+ lymphocytes inside the tumors and in bone marrow, and of CD8+ thymocytes in the medulla of the thymus. Treatment of rats with CPA decreases the activity of lymph cells in tumors, especially of CD4+ lymphocytes. In the spleen, CPA decreases the size of areas related to the production of B and T cells. In the bone marrow, CPA affects the process of myelogenesis and causes significant substitution of cellular components with fatty tissue. The combined treatment with CPA and sTAA increases the number of lymph cells and the apoptotic index in tumors, and restored the rate of B cells producing in the spleen. Similar effect was observed in lymph nodes with accumulation of B lymphocytes in the primary and secondary follicles, and of T lymphocytes in the paracortical zone. In the thymus, CPA alone or in combination with sTAA repairs the inhibitor effect of a carcinogen on synthesis of CD4+ and CD8+ thymocytes. In combined using with CPA, sTAA activate the B- and T-lymphocyte production in the host's immune system and decrease the toxic side-effects of a drug.

Household electromagnetic fields and breast cancer in elderly women.

The relationship between the rate of household low-frequency electromagnetic fields (EMF) and incidences of mammary tumors was studied in 1290 clinical case-records of female patients aged 60 and more over a period of 26 years, based on the materials of the Edith Wolfson Medical Center, Israel. The studied material was divided into two groups, each corresponding to a period of 13 years. Group I included patients with mammary tumors under observation from 1978 to 1990, who rarely used EMF-generating appliances. Group II consisted of patients being under observation in the period between 1991 and 2003, characterized by much more extensive use of personal computers (more than 3 hours a day), mobile telephones, television sets, air conditioners and other household electrical appliances generating EMF. 200,527 biopsy and surgery samples were analyzed. Mammary tumors were found in 2824 women (1.4%), of which 1290 cases (45.6%) were observed in elderly women. Most of the observed tumors--1254 (97.2%)--were epithelial neoplasms. Mammary tumors were found in 585 elderly women in Group I and 705 women in Group II. The case records of these patients showed that 114 elderly women (19.5%) in Group I and 360 (51.1%) in Group II were regularly exposed to EMF (mostly from personal computers) for at least 3 hours a day (chi2=57.2, p<0.001). There was a statistically significant influence of EMF on the formation of all observed epithelial mammary tumors in Group II. This influence is most evident for invasive ductal carcinomas, which was the commonest form of cancer in elderly women.

The soluble p51 protein in cancer diagnosis, prevention and therapy.

The soluble p51 antigen alone, or in combination with the soluble p66 (as a preparation of the soluble tumour-associated antigens, sTAA) was shown to be useful in both cancer detection, prevention and therapy. CANCER DETECTION: In colon cancer patients with recurrent cancer, the blood level of p51 increased whereas the blood level of p66 did not change. The correlation and regression coefficients between the serum level of p51 protein and the progress in colon cancer were 0.48 and 0.88, respectively. In patients with melanoma, development of metastases significantly increased the blood levels of p51. The method was shown to be highly sensitive (92 to 96%) and moderately specific (42 to 65%) for the detection of different types of cancer, such as of the colon, uterus, ovary and breast, as well as melanoma. CANCER PREVENTION AND THERAPY: This was performed using a preparation of both p66 and p51 antigens. sTAA have both tumour-preventive and tumour-suppressive effects on chemically-induced cancers of the colon, skin and mammary glands in rats and mice. sTAA promote suppression of rat mammary tumours by different anticancer drugs, such as cyclophosphamide, tamoxifen and 5-fluorouracil. This effect was shown to be connected with activation of the host's immune system, especially that which is responsible for the activity of T and B lymphocytes. CONCLUSION: We propose the follow-up of cancer patients in order to verify, as early as possible, recurrent cancer and perform preventive therapy of suspect cancer patients with their own sTAA as a kind of autoimmunotherapy. Moreover, in combination with anticancer drugs, sTAA may serve as a new tool in prevention of the toxic side-effects of chemotherapy.

Rat soluble tumor-associated antigens inhibit chemically-induced mammary tumorigenesis in syngeneic rats.

This study examined whether soluble 66 and 51 kDa tumor-associated antigens (sTAA), isolated from the serum of rats with mammary cancer, possess specific suppressive effects on chemically-induced mammary tumorigenesis in syngeneic counterparts. Dimethylbenzanthracene (DMBA, 10 mg/rat, two administrations) was used to induce mammary tumors in 8-week-old Sprague Dawley rats. After the appearance of numerous tumors, preparations of sTAA (50 to 60 microg/rat in 0.5 ml sterile PBS) obtained from breast cancer patients (heterologous sTAA) or from syngeneic mammary tumor-bearing rats (syngeneic sTAA) were administered weekly for 12 weeks. The following groups of mammary tumor-bearing rats were studied: groups 1 and 3, control rats treated with saline; group 2, rats treated with heterologous sTAA; and group 4, rats treated with syngeneic sTAA. The experiment was terminated when tumors in 50% of the rats became ulcerous. The treatment with both types of sTAA significantly decreased, compared to controls and initial values, the yield and total area of the tumors. We conclude that syngeneic sTAA have tumor-suppressive properties, which are very similar to those in heterologous sTAA.

The role of household electromagnetic fields in the development of mammary tumors in women: clinical case-record observations.

BACKGROUND: The relationship between the exposure rates to household EMFs and incidences of mammary tumors has been studied in women based on the materials of the Edith Wolfson Medical Center, Israel. MATERIAL/METHODS: 200,527 biopsy and surgery samples from a period of 26 years were analyzed. The material was divided into two groups: Group 1 included patients with breast tumors from 1978 to 1990 and Group 2 between 1991 and 2003. RESULTS: Breast tumors were found in 2824 women (1.4%). The highest number of tumors was seen in women aged 60 to 69 years. There were 1613 (57.1%) cases in Group 1 and 1211 (42.9%) cases in Group 2. The most frequent malignant cases were invasive ductal carcinomas (1473 of total 2824 cases). These were found in 777 women (52.7%) of Group 1 and 696 women (47.2%) of Group 2. The case records of these patients show that 181 (23.2%) women in Group 1 and 327 (46.9%) in Group 2 were regularly exposed to EMFs (mostly of personal computers) for at least 3 h a day. Despite the significant differences in the number of patients exposed to EMFs for 3 h/day in both groups (chi2=29.7 and p < 0.001), no correlation was found between durable exposure to EMFs and the number of women with malignant tumors in each group. CONCLUSIONS: Results of our studies point to a low potential carcinogenic hazard of low-frequency EMFs.

Response of T and B lymphocytes in the spleen, lymph nodes and mammary tumors in rats treated with human soluble tumor-associated antigens and commercial human albumin.

We showed previously that soluble tumor-associated antigens (sTAA) isolated from breast cancer patients could suppress chemically-induced tumorigenesis in rats in comparison to the effect of commercial human albumin (CHA). Herein we analyze the possible mechanism of those findings. The following groups of mammary tumor-bearing rats were used in the studies: i) control rats treated with saline; ii) rats treated with CHA; and iii) rats treated with human sTAA. Different zones of the spleen, regional lymph nodes and tumors and their cellular content (B and T cells) were analyzed using the methods of morphometry and immunohistochemistry. Treatment of tumor-bearing rats with CHA resulted in a significant decrease in the size of the germinal center of the follicles. The number of B lymphocytes in the mantle layer of the follicles, the marginal zone and red pulp decreased significantly. The number of CD8+ T cells also decreased in the marginal zone and red pulp, whereas the number of CD4+ T cells increased in the periarterial lymph sheath (PALS) and the red pulp. Reaction of the spleen to vaccination with sTAA manifested in a significant increase in the size of most areas of the white pulp and in the number of B lymphocytes. In lymph nodes from control rats or those treated with CHA, CD8+ lymphocytes mainly accumulated in the paracortical zone. In rats treated with sTAA, CD8+ lymphocytes accumulated also in the medulla. The number of CD4+ T cells in these rats sharply increased and accumulated mainly in the medulla around the vessels. The total number of lymphocytes was changed differently in different areas of tumors (peripheral vs. at depth). The number of CD8+ cells significantly increased at depth of tumors, and also the ratio in the number of these cells at depth of tumors compared to a periphery increased. No difference was found in response of lymph cells to different types of treatment. All findings indicated a strict antitumor effect of vaccination with the sTAA, which prevents the development of insufficiency of the immune system when an intensive immune reaction takes place.

Soluble tumor-associated antigens in cancer detection, prevention and therapy.

Soluble tumor-associated antigens (sTAA) with molecular mass of 66 and 51 kDa isolated from the serum of cancer patients was shown can be used for cancer detection, prevention and therapy. CANCER DETECTION: Cancer progression is reflected in the relationship between p66 and p51 compared to healthy people or to patients with non-cancer diseases. The method was shown to be highly sensitive (92 to 96%) and moderate specific (42 to 65%) for the detection of different types of cancer, such as of the colon, uterus, ovary, and breast, as well as melanoma. CANCER PREVENTION AND THERAPY: sTAA have both tumor-preventive and tumor-suppressive effects on chemically induced cancers of the colon, skin and mammary glands in rats and mice. sTAA promote suppression of rat mammary tumors by different anticancer drugs, such as cyclophosphamide, tamoxifen and 5-fluorouracil, and decrease the drug's toxic side-effects. This effect was shown to be connected with activation of the host's immune system, especially those which is responsible for activity of T and B lymphocytes. CONCLUSIONS: We propose the follow-up after cancer patients in order to verify earlier as soon as possible recurrent cancer and perform preventive therapy of cancer suspect patients with their own sTAA as a kind of autoimmunotherapy. Moreover, in combination with anticancer drugs, sTAA may serve as a new tool in prevention of toxic side-effects of chemotherapy.

Response of T- and B-lymphocytes in the spleen of mammary tumor-bearing rats to treatment with tamoxifen and soluble tumor-associated antigens.

We analyzed the role of T- and B-lymphocytes in the antitumor effects of the anticancer drug tamoxifen and soluble tumor-associated antigens (sTAA) on rat mammary carcinogenesis. Studies were performed on the spleen from the following groups of mammary tumor-bearing rats. i) Rats in group 1 were not exposed to DMBA and served as age-related controls. Rats in other groups were exposed to DMBA and received different types of treatment; ii) rats in group 2, received no additional treatment, and served as carcinogen-related controls; iii) rats in group 3 were treated with the commercial hormone-dependent anticancer drug tamoxifen by weekly subcutaneous (s.c.) injections of 10 mg dissolved in 0.5 ml distilled water per rat; iv) rats in group 4 were vaccinated s.c. weekly with a preparation of sTAA (50 micro l/rat) dissolved in 0.5 ml of phosphate-buffered saline; v) rats in group 5 were treated with tamoxifen and were also vaccinated with a preparation of sTAA. Different zones of the spleen were measured and their T- and B-cell contents were analyzed immunohistochemically. The treatment with tamoxifen significantly increased the total number of lymphocytes in the follicles, PALS (periarterial lymph sheath) and red pulp relative to all other groups. The combined treatment with tamoxifen and sTAA increased the areas of white pulp, the PALS, and marginal zone. The number of B-cells was higher in the marginal zone of spleens from age-related controls, as well as from rats treated with sTAA and those treated with tamoxifen and sTAA. The number of CD4+ lymphocytes in the PALS was higher in rats treated with sTAA and tamoxifen, and notably so in those treated with sTAA alone. The number of CD8+ lymphocytes was significantly lower in the PALS of spleens from all tumor-bearing rat groups compared to the unexposed age-related control rats. We suggest that the tumor-suppressive effect of sTAA and tamoxifen is accompanied by the activation of B- and T-lymphocyte production.

Secretory immune system in human embryonic and fetal development: joining chain and immunoglobulin transport (Review).

The role of joining (J) chain, one of the protein components of the secretory immune system (SIS), in the immune reactions of the human embryo and fetus was analyzed on the basis of data from the literature and our previous studies. All organs and structures, including extra-corporeal ones, of 18 embryos (4-8 weeks of development) and 45 fetuses (9-38 weeks) were studied using methods of pathomorphology, immunohistochemistry and morphometry. This approach enabled us to analyze the problem in the whole organism throughout its embryonic and fetal development. J chain, as well as polymeric immunoglobulin (Ig) receptor-secretory component (pIgR/SC) and Igs, are already widely distributed in 4-week-old embryos before the appearance of the common immune system. The whole complex of protein components of the SIS was seen in mucous layers, and in blood-tissue and tissue-tissue barrier structures. Therefore, we can consider two parts of the SIS: mucosal and barrier. Already in embryos, an increase in the functional activity of the SIS following massive antigenic attack in cases of acute chorioamnionitis reflects the increased exocrine secretion of Igs. The J chain appears to participate in the endocytosis but not exocytosis of Igs. J chain and Igs, but not pIgR/SC, were present in cells of the heart, endocrine glands, gonads and some other organs. The exocrine secretion of Igs, the main function of the SIS, is absent in these organs, and, they are therefore, not considered part of the SIS.

Human soluble p66 and p51 tumor-associated antigens promote the suppression of rat mammary tumors in comparison to commercial human albumin.

This study examined whether the soluble 66- and 51 kDa tumor-associated antigens (sTAA), isolated from the serum of breast cancer patients, possess specific suppressive effects on chemically-induced rat mammary tumorigenesis in comparison to commercial human albumin. Dimethylbenzanthracene (DMBA, 10 mg/rat, 2 administrations) was used to induce mammary tumors in 8-week-old Sprague Dawley rats. After the appearance of many large tumors, preparations of sTAA (50-60 micro g/rat in 0.5 ml sterile PBS) or commercial human albumin (HA, in the same doses as sTAA) were administered weekly, for 10-14 more weeks. The following groups of mammary tumor-bearing rats were studied: i) control non-treated rats, ii) rats treated with HA, iii) rats treated with sTAA. The experiment was terminated when tumors in 70% of the rats became ulcerous. The treatment with sTAA significantly decreased, compared to controls, the yield and total area of the tumors. In rats treated with sTAA, the appearance of new tumors stopped at week 5 as compared to week 7 in rats treated with HA and week 10 in control rats. In rats treated with sTAA, the time of appearance of ulcerous tumors increased to 8 weeks, as compared to 6 weeks in controls and in rats treated with HA. Duration of the experiment increased from 11 weeks in controls to 12 weeks in rats treated with HA and to 14 weeks in rats treated with sTAA. We conclude that sTAA have tumor-suppressive properties, which are well-defined if the treatment is begun on small tumors.

Human soluble tumor-associated antigens promote the suppression of rat mammary tumors by 5-fluorouracil and stimulate the functional activity of immune organs: Experimental and morphological studies.

This study examined whether the soluble 66 and 51 kDa tumor-associated antigens (sTAA) could promote suppression by the anticancer drug 5-fluorouracil (5-Fu) of chemically induced mammary tumorigenesis, and which, if any, morphological changes in the immune organs accompany this treatment. Dimethylbenzanthracene (DMBA, 8 mg/rat, twice) was used to induce mammary tumors. After the appearance of many large tumors, the preparations of sTAA and 5-Fu, alone or in combination, were administered in weekly doses, for 4 weeks. The following groups of mammary tumor-bearing rats were studied: 1) control non treated rats, 2) rats treated with sTAA, 3) rats treated with 5-Fu, 4) rats treated with 5-Fu and sTAA. The experiment was terminated when tumors in 70% of control rats became ulcerous. Treatment with sTAA alone significantly decreased tumor yield and their total area relative to controls. Both of these parameters showed an even larger significant decrease after treatment with 5-Fu, and the most marked decrease was obtained after the combined treatment with 5-Fu and sTAA. Results demonstrated that not only do sTAA have tumor-suppressive properties, they also enhance the anticancer effects of 5-Fu and prevent its toxic side effects. Morphologically, the treatment with sTAA was manifested in a significant increase in the size of the spleen follicles and mantle layer compared to control rats with large tumors. The treatment with 5-Fu decreased the sizes of almost all areas of the spleen compared to control rats, whereas the combined treatment with 5-Fu and sTAA increased all these parameters to the levels found in rats treated with sTAA alone. The total areas of the cortex and paracortex in the lymph nodes increased after treatment with sTAA. Treatment with 5-Fu alone resulted in a significant decrease of these areas which, as seen in the spleen, increased after combined treatment with 5-Fu and sTAA. Similar changes were seen in the areas of the separate lymph node zones. We concluded that the addition of sTAA to conventional tumor chemotherapy regimens has a remarkable synergistic effect on mammary tumors leading to curative antitumor responses of the host's immune organs.

Autologous soluble tumor-associated antigens prevent the toxic side effects of cancer chemotherapy and inhibit the progress of tumorigenesis: case report.

In this communication, we report for the first time, that immunization of cancer patients with autologous soluble tumor-associated antigens (sTAA) isolated from their own serum prevents the toxic side effects of chemotherapy, improves the patients' clinical status, and has therapeutic effects without chemotherapy. In 2001 and 2002, two cancer patients were treated, during chemotherapy, with autologous sTAA. Another benign tumor-bearing patient was treated with a medicinal herb and autologous sTAA. Doses for subcutaneous injections varied between 2.5 and 3 mg of sTAA in 0.5 ml of sterile distilled water. Injections were performed twice a week or at weekly intervals. In each case, the clinical status of the patient became more stable and healthier. Toxic side effects caused by chemotherapy decreased or even disappeared. No additional toxic side effects were observed after vaccination with sTAA. In the studied cases, a polyp disappeared and a metastatic brain tumor began to encapsulate. No metastases were seen in the case with colon adenocarcinoma. We concluded that vaccination of patients with autologous sTAA prevents the toxic side effects of chemotherapy in cancer patients and improves their clinical status. In the case with the benign tumor, this vaccination activated the host's immune system, prevented progress of the disease and even promoted tumor disappearance. We suggest that immunotherapy with autologous sTAA provides significant clinical benefits in cancer patients and appears to be an important new adjuvant treatment of cancer.

Epitalon and colon carcinogenesis in rats: proliferative activity and apoptosis in colon tumors and mucosa.

The effect of the synthetic pineal peptide Epitalon (Ala-Glu-Asp-Gly) on proliferative activity in colon tumors, and in mucosal epithelial cells adjacent to and located far from tumors was studied in rats. To evaluate the effect of Epitalon on different stages of carcinogenesis, different treatment regimens were used: during the tumor initiation stage, during the tumor-promotion stage, or during the entire process of tumor development. Eighty 2-month-old male LIO rats were exposed weekly to five subcutaneous injections of 1,2-dimethylhydrazine (DMH) at a single dose of 21 mg/kg body weight. Rats were divided into four groups. Control rats (group 1) received saline at a dose of 0.1 ml during the entire experiment. Rats in group 2 were treated with Epitalon at a dose of 1 micro g, five times a week, for 6 months, from the first injection of DMH till the end of the experiment. Rats in group 3 were treated with Epitalon after termination of the carcinogen injections. Rats in group 4 were treated with Epitalon only during the period of DMH exposure (for the first 5 weeks of the experiment). DMH induced proliferation of the secretory epithelium, and this phenomenon was accompanied by a decrease in the size of the stromal area and the area of lymph infiltration in colon tumors and in the colon mucosa adjacent to the tumors (group 1). Epitalon attenuated this effect, especially when the treatment was continued throughout the experiment (group 2). It increased the stromal areas, as well as that of lymphoid infiltration in the colon mucosa adjacent to the tumors. The intensity of lymphoid infiltration was activated in both the colon mucosa adjacent to a tumor and in the tumor. Mitotic activity of tumor cells was significantly inhibited by Epitalon when the treatment was given throughout the experiment (group 2). In parallel, a high level of apoptosis was seen in the same group. Thus, the strongest inhibitory effect of Epitalon on carcinogenesis in the colon mucosa was manifested when the treatment was continued throughout the experiment.