[Cancer and demographic transition]. / Rak i demograficheskii perekhod.

Two phenomena, one of which relates to the area of human reproduction and the other to the frequency, distribution, and control of disease in a population have emerged in the previous century and continue intensively to develop nowadays. Both these phenomena are directly related to the changes which are occurring in the incidence and prevalence of malignant tumours, as well as to mortality from them and to the opportunities for cancer control. The first of these phenomena has been denominated as the demographic, and the second as the epidemiological transition. The commonly accepted definition of the demographic transition is currently applied to designate a sustainable change in the type of population reproduction, when an initial and abrupt acceleration of population growth is replaced by its rapid deceleration with a subsequent stabilization of a population and a sharp change in its age structure. Demographic transition develops in a brief historical space of time and has the character of a global process. Population ageing and disequilibrium between the younger and older generations are the most important consequences of the demographic transition, and must inevitably influence the strategy and implementation of national cancer control programs. As life expectancy increases, so does the certainty that people will become more and more prone to diseases that are more common among older age groups, i.e. noncommunicable diseases and cancer in particular, rather than being affected by epidemics of infectious diseases. This situation is known as the epidemiological transition and reflects spectacular shifts in the pattern and causes of death and morbidity that have taken place in the vast majority of countries over the previous century. Epidemiological transition results in accession by poor countries to the problems of the rich, and leads to the "double burden" of disease in countries whose economies are undergoing transition, because of the still continuing burden of endemic infectious diseases. Russia is entering the final stages both of the demographic and the epidemiological transition, a period when numerous reasons, increasing demands on the systems of social protection and public health are inevitable. During the years 1992 to 2001, cancer incidence increased from 271.8 up to 313.9 per 100,000 population, i.e. a growth of over 16% and an annual rate of growth of 1.7%. According to the global estimates provided by the International Agency for Research on Cancer the number of new cancer cases in the year 2000 exceeded 10 million, and the number of deaths from cancer reached 6.2 million. The annual growth rate of global cancer incidence during the last 25-30 years was higher than the global population growth rate. Analysis of data available from population based cancer registries in Russia and abroad confirms the conclusion that cancer is mainly the fate of people belonging to the older age groups. Given the levels of exposure to specific carcinogens and genetic predisposition factors, the incidence of cancer should be considered as an exponential function of age. The unfeasibility of attempts to change, in the foreseeable future, the rate and trend of demographic transition and demographic ageing, in particular, is obvious. It would therefore be more feasible to envisage their probable consequences and to adapt the limited resources of national health and social support services to the needs of cancer control, which will significantly increase in the near future.

[The scientific career of V. M. Dil'man]. / O nauchnom puti prof. V. M. Dil'mana.

The life and research career of Prof. V.M. Dilman, who would have been 75 in July, 2000, are briefly outlined. V.M. Dilman had been on the staff of the N.N. Petrov Research Institute of Oncology for many years. He contributed much to the development of oncology, endocrinology and gerontology. Among the basic features of the ontogenetic model of development and aging put forward by V.M. Dilman are the age-associated emergence of hormonal-metabolic factors of increased risk for cancer and relevant measures to be taken to retard this process.

[Modifying effects of changes connected with pregnancy on 1,2-dimethylhydrazine-induced carcinogenesis in rats]. / Modifitsiruiushchee vliianie izmenenii, sviazannykh s beremennost'iu, na kantserogenez, indutsirovannyi 1,2-dimetilgidrazinom, u krys.

The modifying effect of pregnancy and lactation on carcinogenesis induced by single injection of 1,2-dimethylhydrazine to female rats 30 days before mating has been studied. The total incidence of malignant tumours in rats with pseudopregnancy, single pregnancy, pregnancy and lactation, repeated pregnancies was lower in comparison with virgin animals (75, 44, 68, 59 and 93%, respectively). Colon adenocarcinoma incidence in rats with single pregnancy or repeated pregnancies was lower than that in virgin rats (42, 49 and 76%, respectively). Protective effect was observed mainly in descending colon. The mesenchymal kidney tumours were not developed at all in rats with single pregnancy. In virgin animals it was 31%. The inhibition of tumour incidence in the liver (cholangioma, cholangiocellular carcinoma) was observed in rats with single pregnancy or pregnancy and lactation in comparison with virgin control (3, 5 and 24%, respectively).

Influence of hormonal disturbances on transplacental and multigeneration carcinogenesis in rats.

Thyroid dysfunction (induced by thyroidectomy or administration of thyroxin and methylthiouracil) during the postnatal period was tested as a modifying factor on carcinogenesis induced transplacentally by N-methyl-N-nitrosourea (MNU). It resulted mainly in inhibition of tumours of the nervous system and kidney in rats of two subsequent generations, but thyroid carcinogenesis was increased. Postnatal disturbance of oestrous function (induction of persistent oestrus syndrome) in female rats increased the incidence of tumours of the central nervous system induced transplacentally by MNU or 7,12-dimethylbenz[a]anthracene. No such effect was seen in animals of the F2 generation.

5-Bromodeoxyuridine-induced carcinogenesis and its modification by persistent estrus syndrome, unilateral nephrectomy, and X-irradiation in rats.

We showed earlier that 5-bromodeoxyuridine (BrdUrd), which can substitute for thymidine during DNA synthesis, inducing transition mutations, is incorporated into DNA of various tissues when administered to newborn rats and is not subjected to repair processes. The main purpose of the present experiment is to verify if a direct perturbation of DNA would be sufficient to initiate carcinogenesis. Rats aged 1, 3, 7, and 21 days were given BrdUrd s.c. at a dose of 3.2 mg/animal. At 2 months some of the females were subjected to treatment known to induce persistent estrus; at 1 month a group of males underwent removal of one kidney, and groups of males and females were exposed to a single total-body X-irradiation at a dose of 1.5 Gy (150 rads) per rat. In females, treatment with BrdUrd induced tumors of the ovaries, polyps in the uterus, and tumors of the soft tissues, nervous system, forestomach, glandular stomach, and salivary gland; no such tumor occurred in control females. Induction of persistent estrus increased the incidences of ovarian tumors and of malignant tumors of the uterus. Treatment with BrdUrd also increased the carcinogenic effect of X-rays on the mammary gland. In males, BrdUrd induced tumors of the testis (seminomas) and adenomas of the thyroid gland; solitary tumors of the kidney, nervous system, soft tissues, and bladder were also found. Unilateral nephrectomy reduced the incidences of tumors in the testis and pituitary gland, whereas subsequent treatment with X-rays did not alter the incidences of tumors induced by BrdUrd. These studies demonstrated for the first time that a nucleoside analogue, BrdUrd, has carcinogenic potential. Possible molecular mechanisms for its carcinogenicity and for the effects of the promoting factors are discussed.

[Effect of disordered thyroid function on the realization of the transplacental carcinogenic action of N-nitrosomethylurea in 1st- and 2d-generation rats]. / Vliianie narusheniia funktsii shchitovidnoi zhelezy na realizatsiiu transplatsentarnogo kantserogennogo deistviia N-nitrozometilmocheviny u krys pervogo i vtorogo pokolenii.

The F1 rats subjected to the influence of N-nitrosomethylurea (NMU) in dose of 20 mg/kg on the 21 day gestation as a result of postnatal disturbances of the thyroid function induced by long administration of thyroxin (3 mg/100 g, daily), methylthiouracil (MTU; 0.1% solution in tap water) or thyroidectomy have shown a decreased incidence of the nervous system tumours, but not of the kidney tumours, i. e. sites typical of NMU transplacental carcinogenesis. At the same time the NMU transplacental effect increased thyroid carcinogenesis, induced by the MTU postnatal application, which manifested in the increased incidence of malignant tumours of this site. The carcinogenic effect was observed in F2 rats, while some of them developed tumours of the nervous system (14.9%) and kidney (8.5%) but with lower incidence than in F1 (35.4; 14.1%, respectively). The same modifying factors (thyroxin, thyroidectomy, MTU) employed under the same conditions produca similar effect on carcinogenesis in F2 animals.

Prenatal and childhood exposure to carcinogenic factors.

Transplacental carcinogenic effects have been demonstrated for about 60 chemicals in eight animal species and even in the human. Many carcinogens are much more active in the fetus than in the adult animal. The stage specificity of transplacental carcinogenesis is characterized by the possibility of inducing tumors only at certain stages of embryogenesis (at the end of organogenesis and during the whole period of histogenesis). Risk of transplacental carcinogenesis is owing to the passage of carcinogens or their active metabolites into embryonic tissue and the possibility of metabolic activation of substances within the fetus. In this connection, four main pathways can be hypothesized for the carcinogenic effect of a substance on the fetus. Organotropism with transplacental carcinogenesis is determined by genetic predisposition, differentiation, and proliferative activity in the target tissues. For indirect carcinogens the level of metabolizing enzymes is also important. Teratogenesis and carcinogenesis can be either independent processes or pathogenetically related to each other (eg, DES action). Experimental data can readily be applied to the discussion of prophylaxis of prenatal tumors in the human.

[Modifying effect of thyroid gland functional disorders on realization of transplacental carcinogenesis induced by N-nitrosomethylurea in rats]. / Modifitsiruiushchee vliianie narusheniia funktsii shchitovidnoi zhelezy na realizatsiiu transplatsentarnogo kantserogeneza, indutsirovannogo N-nitrozometilmochevinoi u krys.

The paper discusses the influence of deranged function of the thyroid (in postnatal period) on the transplacental carcinogenic effect of N-nitrosomethylurea (NMU) in albino noninbred rats. It was found that exogenous thyroxin-induced hyperthyroidism and thyroid function suppression either by long-term treatment with a thyreostatic agent--methylthiouracil (MTU) or thyroidectomy are followed by a lower frequency of, chiefly, nervous system tumors which are typical of NMU-induced transplacental carcinogenesis in rats. Moreover, transplacental treatment with NMU potentiated the carcinogenic effect of MTU on the thyroid. The latter manifested itself in a higher frequency of malignancies of the thyroid in animals exposed to a combined treatment with NMU (transplacentally) and MTU (postnatally) as compared with those given MTU only (postnatally).