Von Recklinghausen's disease, or neurofibromatosis type 1 (NF-1), is an autosomal dominant syndrome with a highly variable tumorous (neurofibromas, gliomas, Wilms' tumors, leukemia, pheochromocytomas) and non-tumorous (cafe-au-lait skin spots, iris and ciliar hamartomas, osseous lesions) manifestations. NF-1 gene is mapped to chromosome 17. Central or bilateral acoustic neurofibromatosis (NF-2) has a gene mapped to chromosome 22. Hereditary and sporadic NF-1 are recognized. The most typical manifestation of NF-1-skin neurofibroma--has has a characteristic plexiform structure. Spectrum of tumors (schwannomas, gliomas, Wilms' tumors) produced by transplacental treatment with strong environmental mutagens-carcinogens-ethylnitroso- and methylnitrosourea (ENU and MNU, respectively) resembles on the whole that observed in human sporadic NF-1. Location of neurofibromas depends on the species: skin and subcutaneous tissue in humans, cattle and hamsters, trigeminal nerve, spinal roots in rats. Rat schwannomas differ from human neurofibromas by malignant structure, frequently with cystic component, but if induced by ENU treatment at day 15 of the pregnancy they resemble human plexiform neurofibromas with intraneural and extraneural growth of tumor cells. There were attempts to reproduce a transgenerational transmission of ENU carcinogenic effect, i.e. hereditary form of NF-1. In the experiments of this type the offsprings of rats prenatally treated with ENU remained untreated. The incidence of PNS, CNS and Wilms' tumors in these untreated offsprings in some experiments was significantly higher than in controls thus confirming the possibility, in principle, of hereditary NF-1 modelling. Only 10% of tumors developing in such untreated descendants of ENU treated parents contained a specific mutation of neu oncogene compared to 90-100% in tumors arising following direct treatment with ENU. The mechanisms of the transgenerational carcinogenesis are discussed. Lesions imitating NF-1 and in part NF-2 in transgenic mice with an HTLV-1-tax gene as well as in p-53 knockout mice are mentioned.

The comparative heterozygosity level was estimated in patients suffering from squamous epithelial lung cancer (SELC) and in patients with chronic pneumonia with bronchiectases. To estimate heterozygosity, seven loci, reflecting normal diversity in human populations, were used (HP, TF, GC, PI, GL01, ACP1, PGM1). SELC patients with an uncomplicated postoperative period were distinguished by an increase in the level of observed heterozygosity (Hzero = 0.3916) in comparison with the theoretically expected value (H(e) = 0.4361). Patients having chronic pneumonia with bronchiectases with a complicated postoperative period were distinguished by an increase in the observed and expected level of heterozygosity (Hzero = 0.3737, H(e) = 0.3837) in comparison with that in the patient cohort with an uncomplicated postoperative period. The Wright's fixation index had a high value in the SELC cohort with an uncomplicated postoperative period (F = 0.1073) and a low value in patients with complicated cases (0.0048), witnessing the polar divergence of those patients from the total group of patients (0.0598) and the control (0.0388). The D criterion, reflecting deviation from the maximum heterozygosity level, distinguished the SELC patient cohort with a complicated postoperative period from patients with uncomplicated cases by the HP, GC, and ACP1 loci. The D criterion distinguished the SELC patients from the healthy control groups by the PGM1 locus.

A comparative study was made of transplacental (in vivo) and direct (in vitro) effects of benz(a)pyrene (BP) in the organ cultures of embryonal lungs of mouse susceptible (strain A) and resistant (C57 Bl) to pulmonary blastomogenesis. The development of the epithelium squamous cell metaplasia was observed only after direct application of BP on the lung explants in vitro. Correlation between metaplasia frequency and BP dose and duration of treatment and mouse susceptibility to pulmonary blastomogenesis is established. Thus, at all BP concentrations (3.6 or 12 micrograms/ml of medium) and maximum time of treatment (15 days) the frequency of squamous cell metaplasia in the lung explants of C57 B1 mice was very low (3.0, 2.0 and 4.2%, p > 0.1) while in a strain A it was significant at the doses of 6 and 12 micrograms/ml (10.4 and 23.4%, p < 0.001). No epithelial metaplasia developed when the time of BP treatment was decreased up to 7 days.

The authors' material (33 tumours) and that from foreign literature (18 to 100 tumours from every country) was used. The following chromosome aberrations were compared: the deletion of a part of chromosome 1 short arm, deletion of chromosome 5 and a part of its long arm, additional chromosomes 7, complete or partial deletion of chromosome 17 short arm, deletion of chromosome 18 and appearance of additional chromosomes 20. Clear-cut differences were revealed between the following three groups of regions: 1) countries of the Eastern and Western Europe (Russia, France, Germany); 2) Northern Europe countries (Denmark, SWeden); 3) USA and China. Geographical differences in chromosome anomalies in hemoblastosis were found in 1970s, the difference in colon carcinoma are presented for the first time. The experimental results suggest that non-homogeneous distribution of the karyotype alterations typical for certain morphological types of malignant tumours are due to different environmental influences.

A case of metachronous cancer of gastrointestinal tract is reported. Three poorly differentiated malignant epithelial tumours developed in a 27-year-old patient within three years. They located in the stomach, small and large intestine. Light-microscopically, the tumours were formed mainly of non-differentiated rounded cells with occasional signet ring cells. At electron microscopic examination the presence of mucin granules was confirmed. Moreover, a variable amount of electron-dense endocrine-like granules was found in tumour cells. According to some publications, endocrine differentiation of gastrointestinal cancers is considered to be a poor prognostic feature, hence electron microscopy or special staining when possible can be important in the evaluation of prognosis.

Systemic clinical and molecular-biological analyses of cause-effect relations between human papillomatosis virus (HPV) and juvenile respiratory papillomatosis (JRP) disclosed general mechanism of HPV infection initiation and stages of tumor genesis. However, there is no consent on the universal etiopathogenetic approach to the disease treatment. The authors give some results to the disease treatment. The authors give some results of present-day combined treatment of JRP which includes surgical removal of papillomas and modulation of immunity by interferon preparations.

Using subtractive hybridization, a cDNA library containing over 50% of clones specific for a highly metastatic cell line was obtained from two hamster embryo fibroblast lines with different metastatic potentials. Most of the clones (83%) contained new sequences. One clone contained the ha-SDGF gene cDNA homologous to SDGF cDNA from rodents. The level of ha-SDGF mRNA expression was considerably higher in the highly metastatic cell line.

Two lines of fibroblasts isolated from patients with homocystinuria were characterized by the test of vaccinia virus host-cell reactivation. Xeroderma pigmentosum cells and normal fibroblasts were used as a control. Reduced host cell reactivation of the virus and an enhanced level of induced virus mutations in comparison with normal cells were revealed in homocystinuria cells after 4NQO and gamma-ray treatment. Enhanced reactivation and a corresponding reduced level of gamma-induced mutagenesis were found in preirradiated normal cells and in the xeroderma pigmentosum cells. The level of enhanced reactivation of the virus was virtually the same in preirradiated and nonirradiated homocystinuria cells, while the level of induced mutagenesis was reduced in both cells. This indicates the difference in the capability of the virus system for enhanced reactivation to repair potentially lethal and premutational DNA damages.

The prime focus of cancer epidemiology is the study of causal relations between exogenous exposure and clinical cancer. Molecular epidemiology is a promising new tool in the study of environmental carcinogens. Techniques of molecular epidemiology can be applied in assessing: internal "biological effective" dose by measuring carcinogen-DNA adducts; variation in individual susceptibility to carcinogens; carcinogen-specific genetic lesions for identification of tumorigenic chemicals in complex mixtures; early biologic effect, particularly mutations and other damage in cellular genes (molecular precancer), likely to be predictive of cancer. By incorporating biologic markers into epidemiologic studies, one can detect potential hazards early and increase the statistical power of studies to determine causal relationship. Such markers can also improve extrapolation of risks from experimental animals to humans.

Genetic polymorphism at 10 independent loci (ABO, RH, HP, GC, PI, TF, ACP1, PGM1, GLO1, and PTC) was studied in male patients with lung squamous cell carcinoma. These patients were divided into two groups, depending on their tolerance for surgical intervention and on the postoperative course: (1) patients with an uneventful postoperative period and (2) patients with postoperative complications. The genetic structure of the combined sample at the loci studied did not differ from that of the control group consisting of health people (population control). Genotypic differences might manifest at the postoperative stage rather than at the onset of the disease, and determine the presence of postoperative complications. However, comparative analysis of the two groups of patients revealed their polar divergence in respect to phenotype and gene frequencies at certain loci. Moreover, the genotypic structure of patients in both groups differed from that in the combined sample and in the population control. In the group with postoperative complications, higher frequencies of the alleles GC*1F, ACP1*A, and HP*2 were observed. By contrast, the group of patients with an uneventful postoperative period demonstrated prevalence of the alternative alleles of these loci: GC*2, ACP1*B, and HP*1. The greatest difference in the distribution of informative allele frequencies was observed between the group of patients with postoperative complications and the control group. This is evidence that these groups significantly differ in their genetic structure. Such divergence is largely determined by the polymorphic multifunctional systems of serum proteins.

DNA damage of the tumor cells was studied by the method of alkali elution from filters after introduction of 1-methyl-1-nitrosourea (MNU) and 1,3-dimethyl-1-nitrosourea (DMNU) to mice with Ehrlich ascites carcinoma or after treatment of the cultivated cells with these drugs. DNA was essay fluorometrically using DAPI. The degree of DNA damage was characterized by the constant of the alkali elution rate (Kae), which was estimated according to the anamorphism of the kinetic curves of elution. It was shown that in the case of MNU application the tumor cell DNA was damaged to a greater extent than in the case of DMNU application. Kae increased with the concentration of drugs. A correlation was established between the antitumor activity of the drug (kappa), K(ae), and the number of chromosome defects per cell (gaps, deletions, microfragments, ring chromosomes, and translocations). This suggests that kappa is due both to DNA damage and chromosome defects.

Small antisense RNA (alpha-RNA), components of a new class of small nuclear and cytoplasmic RNP (alpha-RNP) identified in the cells of K-562 human proerythroleukemia cell line, are capable of hybridizing under stringent conditions with precursors of mRNA (heterogeneous nuclear RNA or mRNA) and with mRNA of these cells. We found that DMSO, an agent inducing differentiation in K-562 cells, is capable of regulating the composition of alpha-RNA population and concomitantly changes the content of mRNA that has regions homologous (complementary) to alpha-RNA. Specifically, it has been demonstrated that DMSO decreases the level of alpha-RNA, which hybridizes with the actin gene. Results of restriction mapping of regions of complementary interaction of alpha-RNA with the actin gene point out that alpha-RNA hybridizes with regions containing the promotor area and 3'-nontranslated area of the gene. It is proposed that small antisense alpha-RNA (alpha-RNP) participates in the control of gene expression at posttranscriptional level in cell cytoplasm.

A new class of small RNP (alpha-RNP) has been detected and identified in nuclei and cytoplasm of A-562 erythroid leukemia cell line; these RNPs have a characteristic spectrum of proteins containing conservative and specific components and a special RNA component, which contains a small antisense component (alpha-RNA), a homolog of short dispersed Alu repeats. alpha-RNP is highly stable, tightly associated with chromatin in the nucleus, and is found in the free state in cytoplasm. The composition of nuclear and cytoplasmic alpha-RNP differ and have a specific pattern of changes in response to dimethylsulfoxide, an agent causing differentiation.

Selection in vivo of cell clones of rat transplantable organospecific rhabdomyosarcoma RA-23 for increased and decreased frequencies of cells with chromosomal bridges (FCB) was performed. The initial average FCB in clones was 0.8% at a range of variation of from 0 to 3.0%. Selection for an increase, as well as for a decrease, in the FCB in RA-23 clones was effective. After one step of selection for an increase in the FCB, the average FCB increased to 3.0%. Thereafter, selection for an increase in the FCB was impracticable due to loss of transplantability in cell populations in which the FCB exceeded 5.0%. Over five steps of selection for a decrease in the FCB, the average FCB significantly decreased to 0.3% (P < 0.001). The heritability coefficient h2 of the trait FCB upon selection ranged from 0.25 to 0.30. The high and low FCBs attained by selection correlated with the index "frequency of cells with micronuclei." The population of RA-23 cells after selection for a decrease in the FCB differed from the population of cells of the original RA-23 strain by significantly lower karyotypic heterogeneity. The values of h2 obtained upon selection for the FCB and the effectiveness of selection for an increase, as well as for a decrease, in the FCB show that, with selection at the trait "frequency of cells with bridges," which characterizes the stability of the karyotype, existing cell strains can be subjected to karyotypic stabilization or destabilization.

Development of apoptosis was followed up in the cell line LIM-1863 of human colon carcinoma and in the same cell line with multiple drug resistance (MDR) related to the expression of gene mdr I and hyperproduction of protein P-glycoprotein 170 encoded by this gene. The number of cells with histological and ultrastructural features of apoptosis increased with acquirement by tumor cells of typical MDR. The enhancement of apoptosis in tumor cells with MDR results probably from the increase of cells with signs of terminal differentiation which is one of apoptosis inducers. Mitotic activity in both lines did not change essentially, but the original line had a more rapid growth than its analogue with MDR. Elimination of cells through apoptosis may be the cause of slower growth of the cell line with apoptosis. The rate of tumor growth depends on the balance between proliferative activity and apoptosis.