This review deals with a phenomenon of multigeneration carcinogenesis; the carcinogenic risk for offsprings of irradiated persons can be estimated as 4.10(-3) Sv-1. Though some epidemiological findings in this area are contradictory, multigeneration carcinogenesis may present a part of a population risk (genetic load). There is a need for recording the phenomenon in the normal ranges of radiation safety, i.e. to limit the planned irradiation of males aged 30-40 years, as well as females of the same age.

The problems of anticarcinogenesis are discussed in the context of mechanistic approaches and the well-known mechanisms of multistage carcinogenesis. Various events at extra- and intracellular levels are involved in mutagenesis and carcinogenesis. The most promising candidates for suppression of chemical carcinogenesis are some nitrosation modifiers, dietary sorbents, metabolic activation modulators, reactive metabolite trappers, repair inducers, gene expression inhibitors, etc. Short-term tests for mutagenicity are more preferable for screening potential anticarcinogenic agents. The bioassays for anticarcinogenesis should be assessed for sensitivity, specificity and predictability and the genetic profiles of the antimutagenic activity of the modifiers analysed.

The first intron of the mts1 gene, a gene which is selectively expressed in metastatic cells and in normal cells that are motile, was found to be highly homologous to the CD3 delta enhancer element. Because of the homology between the CD3 delta enhancer and the first intron of mts1, we analysed the first intron of the mts1 gene to determine whether it functions as a transcriptional regulatory element. Highly metastatic CSML-0 cells transfected with chloramphenicol acetyltransferase containing plasmids demonstrated the ability of the mts1 first intron to function as a positive regulatory element. In vitro footprinting analysis using extracts from CSML-0 cells (which express mts1 at low levels) of CSML-100 cells (which express mts1 at high levels) identified a protected 16 nucleotide element in the first intron of mts1, regardless of the extract used. However, in vivo footprinting analysis of the same region identified the protected 16 nucleotide fragment only in the mts1 intron from CSML-100 cells, not from CSML-0 cells. Differences in the methylation pattern of the mts1 gene in CSML-100 cells and CSML-0 cells are known to exist, and may in part be responsible for the mts1 footprinting differences observed in vivo from the different cells lines.

The effect of oxythiamine (400 mg/kg) on chromosomal structure of Ehrlich ascites carcinoma cells (EAC, hyperdiploid strain) and bone marrow cells was studied in intact AF mice. The influence of the antivitamin on the rate of tumor growth was investigated in tumor-bearing mice. Oxythiamine decreased transketolase activity in hepatocytes and tumoral cells and markedly inhibited tumor growth. Amount of chromosomes was unaltered both in tumor cells and in bone marrow cells, which could be manifested as increased content of cells with impairment of chromosomal set calculated per a cell. However, the oxythiamine-induced impairment of chromosomal integrity was less distinct as compared with the effect of such mutagens as urethane and cyclophosphamide; hence, the antivitamin might be used in the courses of combined chemotherapy.

Abnormalities of some oncogenes, antioncogenes and losses of heterozygosity (LOH) of chromosome 11p, 17p, and 17q in colorectal carcinomas (CC) was studied. Amplification of ERBB-1/HER-1 oncogene was detected in 2 of 56 cases; ERBB-2/HER-2- in 4 of 62. There was a lack of evidence for C-MYC oncogene amplification (67 cases). LOH of chromosome 11p (HRAS-1 probe) was found in 2 of 37 informative (heterozygous) cases; such events were not accompanied by point mutations in "hot" codons (12th or 61st) in the remaining allele. Prevalence of A3 and A4 alleles of HRAS-1 oncogene (68 cases) as compared to healthy donors was noted. RB-1 (41 cases) and p53 (62 cases) suppressor genes did not show any alterations in Southern-blot analysis. LOH of chromosome 17p (YNZ-22 probe) was found in 15 of 26 heterozygous CC; 17q (THH-59 probe)--in 4 of 16. Analysis of 175th codon of p53 gene revealed only one case of mutation in 35 CC studied. Finally, we were able to detect genetic alterations in 23 of 40 (58%) CC, that were studied on each parameter using Southern-blot. We failed to find any correlation between various molecular abnormalities or clinical characteristics. The data obtained are in disagreement with the view concerning frequent involvement of p53 antioncogene in chromosome 17p deletions.

Mutant clones of hepatocarcinoma cell line PLC-PRF-5 containing integrated hepatitis B virus genome were derived by multistep selection for resistance to some toxic agents. These clones were found to display various stages of cell differentiation according to growth rate, ability to synthesize alpha-fetoprotein, to grow in semisolid medium and to cloning in agar. In the majority of the clones with higher stages of differentiation the expression of HBsAg gene was demonstrated to be increased as compared to the original line, and in some of these clones the expression of silent HBcAg was activated.

The role of the activated oncogene c-Ha-ras-1 from human bladder carcinoma integrated into the pEJ6.6 plasmid in the mutagenic effect of the plasmid was studied in Chinese hamster cells. The frequency of hypoxanthine-phosphoribosyltransferase defective (HPRT-) mutants after treatment with pEJ6.6 containing an active c-Ha-ras-1 exceeded that in control dishes treated with a derivative of pEJ6.6 plasmid with an inactivated oncogene. The inactivation was achieved by introducing a deletion into the coding region of the oncogene. The mutagenic effect was rather weak but statistically significant. Thus, the data obtained show that the mutagenic activity of pEJ6.6 plasmid is determined by its oncogene. The role of mutagenic effects of activated cellular oncogenes in malignant transformation is discussed.

There is no single point of view on pathogenesis of hemangiomas. The authors investigated the ABO blood types in 52 patients with hepatic hemangiomas (Group 1) and 1000 control patients (Group 2). The study demonstrated 61.5% of the A blood type among the patients of Group 1. This was significantly higher than in the Group 2 and representative groups from literature (P less than 0.001). Taking into account that the cells of both blood and blood vessels are formed in embryos through the mesenchyma and the heritability of blood group antigens, it is supposed that the results obtained support the genetic determination theory of pathogenesis of hepatic hemangiomas.

The induction of gene mutations and chromosome aberrations by the plasmid pEJ6.6 carrying the activated c-Ha-ras-1 oncogene from human bladder carcinoma was studied in cultured Chinese hamster cells. Both an increase in the frequency of gene mutations to 6-mercaptopurine resistance and of chromosome aberrations was observed after pEJ6.6 treatment as compared to control series (pBR322). Thus the results of experiments carried out show that the pEJ6.6 plasmid possesses a mutagenic activity.

The investigation concerning the dependence of cancer incidence on genetic HLA-markers and character of dermatoglyphs was carried out. The use of the pattern recognition method for multifactorial estimation of the above markers as well as the elimination of the main non-genetic oncogenic risk factors allowed obtaining the proof of the existence of the genetic predisposition to lung cancer. It was estimated that the character of dermatoglyphic prints is the most adequate marker for the investigated predisposition, and the reliable prediction of the genetic risk of the lung cancer development can be given as based on the joint evaluation of both markers.

Clinical-genetic examination of 305 patients with multiple primary tumors aimed at determining the rate of genetic burden to their development and community of joint accumulation of tumors in families of these patients has revealed a significant genetic community of inheritance of breast cancer, carcinomas of colon, endometrium, ovaries and stomach in the families of patients with multiple primary tumors. Comparative analysis of genetic correlations has shown the greatest genetic burden in families of patients with multiple primary tumours as against the families of patients with solitary cancer.

A total of 64 patients with genital endometriosis were examined. The reference group included 120 phenotypically healthy women. The dermatoglyphic pattern of patients with genital endometriosis was defined, pointing to a genetic predisposition to genital endometriosis and reflecting the risk of its development. Together with other clinical and laboratory criteria, the dermatoglyphic studies permit an early diagnosis of endometriosis.

It is shown as necessary to create specialized aid to cancer families in the general structure of oncological service. The results of 2-year clinical-genetic monitoring of high-risk group relative to ovarian, breast and endometrial cancer are presented.

The dependence of UV-induced unscheduled DNA synthesis (UDS) in non-stimulated lymphocytes of human peripheral blood on the ionic strength (mu) of the culture medium has been shown. With the level of mu lower or higher than physiological (mu ph) the UDS significantly decreases. The effect of modification of mu due to changes in ionic strength is absent in the lymphocytes of patients with the classic form of xeroderma pigmentosum. This phenomenon may become useful for development of a new test revealing cells with genetically or physiologically changed system of UV-induced DNA repair. Mechanisms of investigated phenomenon, particularly their dependence on the chromatin structure, as well as the influence of ionic strength on binding the repair enzymes with DNA are discussed.

Two aspects can be distinguished in multistage carcinogenesis: etiological one (every stage is induced by a specific for this stage agent) and morphobiological aspect (every stage is characterized by specific morphological, genetic and other properties). The schema of the multistage carcinogenesis is presented in which morphological stages (diffuse and focal hyperplasia, benign tumours, dysplasia, carcinoma in situ, various phases of malignant tumour progression) are placed against genetic alterations. L. Foulds concept of tumour progression is discussed with special emphasis on precancerous stages, possibilities of cancer development de novo, and independent progression of different tumour characters. The following types of carcinogenesis are listed on the basis of interrelationship between etiological and genetic factors: 1) carcinogenesis induced by genotoxic agents; a) one agent is acting at high dose and for a long time thus ensuring the activation of protooncogenes and all stages of tumour progression (initiation, promotion, various phases of malignant tumour); b) those acting during a very short time, however sufficient for developing the genetic program working automatically without further exposure to known carcinogens (irradiation in case of the atomic bomb explosion or effect of short-living alkylating agents): in this case there is no stage of promotion; 2) carcinogenesis by non-genotoxic carcinogens (their mode of action is still unclear, the only human example is carcinogenesis by hormones); 3) development of tumours in frane of the two (or three) stage carcinogenesis when every stage is provoked by its own etiological factor, no human examples are known as yet; 4) development of tumours due to the genetic mechanism making the organism highly susceptible to the minimal doses of carcinogens as is the case with skin cancer by ultraviolet light in patients with xeroderma pigmentosum, the genetic damage in itself has nothing to do with tumour formation; 5) genetic damage leading to the development of tumour without visible participation of any known carcinogens or promoters (gene Rb in retinoblastoma, gene Wt in Wilms tumour, etc.).

A cytogenetic observation, that the sister chromatid exchanges (SCE) occur 3 times more frequently in a special form of xeroderma pigmentosum--XPII than in the norm, prompted a study of DNA replication in this rare disease. Using DNA fiber autoradiography, the rate of fork movement and the frequency of initiation in the adjacent clusters of replicons were estimated. The rate of fork movement was significantly slower than that in classical XP and in normal cells. Here evidence was provided on another defect in DNA replication in XPII that involves a significantly decreased number of simultaneously operating adjacent clusters of replicons, which results in a decreased rate of DNA chain-growth. According to the Painter replication model for SCE, the exchanges arise due to double-strand DNA breaks occurring on the border between two adjacent clusters, respectively, completely and partially replicated. A retarded fork-displacement rate together with a decreased rate of DNA-chain growth may cause this situation to persist longer than in the norm. Thus, our data provide a further support of the replication model for SCE. A similar combination of cytogenetic and molecular defects has been obtained earlier in the Bloom syndrome cells.

The argyrophilic staining of nucleolar organizer regions (AgNOR) has been found to be of increasing use in routine and experimental histopathology in the study of certain neoplastic lesions. The AgNOR reaction demonstrates the presence of argyrophilic non-histone proteins within NORs. The number of detectable NORs depends on several factors: the level of transcriptional activity, the number of NOR-bearing chromosomes in the karyotype, and the stage of the cell cycle in which they are sought. In man, five chromosomes have NORs, and these areas are the sites which hybridize with rRNA and are of importance with respect to the ultimate synthesis of protein. The results of AgNORs might be more informative if this technique would be applied simultaneously in cytological and histological specimens for each patient. It may also be important to examine the AgNORs profiles in stromal cells.