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In vivo adduct formation by benzo[a]pyrene (BP) has been compared in mouse and rat epidermal keratinocytes and dermal fibroblasts after topical application of an initiating dose of carcinogen. The BP-DNA adducts were analyzed by chromatography and acid hydrolysis of BP-deoxyribonucleoside adducts to BP-tetrols. BP was dissolved in acetone and applied, at similar doses per unit area (100 nmol/mouse and 240 nmol/rat), to 50-day-old Swiss mice and 35-day-old Wistar rats. Epidermal and dermal cells were isolated twenty four hours later. Reverse-phase HPLC of BP-deoxyribonucleoside adducts demonstrated the presence of three BP-deoxyribonucleosides adducts in mouse epidermal cells and one in mouse dermal cells. An unknown product (0.13 and 0.04 pmol/mg mouse epidermal and dermal cell DNA respectively) eluted before the BP-7,10/8,9-tetrol marker, at same relative position as 9-OH-BP-DNA adduct. The major adduct formed in mouse epidermal keratinocytes and dermal fibroblasts was dGuo modified by (+)-anti-BPDE and accounted for more than 70% of the adducts. Acid hydrolysis of the individual BP-DNA adducts was used to identify the BP-DNA adducts formed in mouse epidermal and dermal cells as anti- and syn-BPDE-dGuo. Twenty four hours after topical application of BP, the total levels of modified deoxyribonucleosides and (+)-BPDE-dGuo were 3 times greater in mouse epidermal cells than in dermal cells. The ratios of anti-BPDE to syn-BPDE was 17:1 and 12:1 in mouse epidermal and dermal cells DNA, respectively. This work provides the evidence that, at an initiating dose, 3H modified deoxyribonucleosides of rat epidermal keratinocytes and dermal fibroblasts are not detectable. This may be essential for the resistance of rat skin to the carcinogenic action of benzo[a]pyrene.

On rats hypothermia of 22 to 20 degrees C and rewarming to normal body temperature leads to an amplification of the hyperglycemic tumor acidification. Mechanism and significance of this effect are discussed.

Certain backcross hybrids (BC8-22) of a spotted X. maculatus (platyfish) and a non-spotted X. helleri (swordtail; recurrent parent) are highly sensitive to mutagenic carcinogens and, after a latent period of 8 to 12 months, develop melanoma of unicellular origin that is genealogically related to the spots of the platyfish. Sensitivity to the carcinogen or susceptibility to melanoma, respectively, are inherited in a Mendelian fashion and can be assigned to a "tumor gene-complex" (Tu-complex) consisting probably of almost 20 genes. The Tu-complex is located at the end of an autosome or sex chromosome, and is largely deregulated by crossing conditioned replacement of platyfish chromosome carrying regulatory genes (tumor suppressor genes, oncostatic genes, antioncogenes) for the Tu-complex by swordtail chromosomes lacking them. The melanoma-free condition of these BC-hybrids depends upon the skin-specific regulatory gene Bs (body side) that requires impairment in a pigment cell precursor for the outgrowth of melanoma. Structural mutations involving different breakpoints indicate that the signal for melanoma formation comes from a particular region of the Tu-complex where an accessory v-erb B related oncogene (x-erb B*a; 85% homology to the human EGF receptor gene) is located. Northern blot analyses of the melanoma cell line showed an about 20-fold overexpression of x-erbB*a. Both the inositol lipid turnover [(3H)inositol incorporated into phosphoinositides], and the xiphophorine pp60x-src kinase activity that are assumed to be causally involved in tumor formation showed a remarkable elevation in the melanoma as compared to the normal tissue (brain) of the tumorous and non-tumourous (with or without the Tu-complex) segregants. Other BC hybrids carrying the Tu-complex but lacking the linked regulatory gene develop melanoma "spontaneously". This kind of melanoma occurs early in the course of life, is of multicellular origin, and is inherited as a Mendelian character. In contrast to the BC hybrids requiring somatic mutation for melanoma formation, both inositol, lipid turnover and x-src activity are remarkable enhanced in both melanoma and normal tissues. A mutant of the laller BC hybrids carrying in addition of the Tu-complex the homozygous oncostatic gene g (g/g, "golden") that arrests pigment cell differentiation in the stem cell stage is incapable to develop melanoma spontaneously. Nevertheless it shows the elevation of inositol lipid turnover and x-src activity in its always healthy tissues. Following treatment with tumor promoters such as TPA and steroid hormones pigment cell differentiation recovers and melanoma of multicellular origin develops within 4 to 8 weeks.(ABSTRACT TRUNCATED AT 400 WORDS)

The hamster polyomavirus was first isolated by Graffi et al. in Berlin-Buch from skin epithelioma arising spontaneously in the Buch Syrian hamster colony. Virus particles are assembled in the nuclei of keratinized cell layer. The genome organization is identical to the murine polyomavirus genetic map including, in particular, the existence of a coding capacity for an early gene product analogous to the middle T antigen. The virus and the cloned DNA can immortalize primary cells and transform established cell lines from rodent origin. The HaPV can also induce lymphoma and leukemia after inoculation into newborn animals from a Potsdam Syrian hamster colony geographically separated from the colony affected by the spontaneous epitheliomas. The tumor incidence is high (30-80%), the latency short (4-8 weeks). The lymphomas are virus free but contain large amounts of nonrandomly deleted viral genomes. Transgenic mice produced by microinjection of HaPV DNA into the pronucleus of fertilized eggs of Gat: NMRI mice develop both, epitheliomas and lymphomas. The mice tumors contain extrachromosomal viral DNA. A search for a cellular host fully permissive for HaPV productive cycle in vitro lead to the conclusion that the hamster cells represent the most permissive context for the HaPV genome replication; however, in only one cell line the virus can be propagated by successive productive cycles leading to the establishment of a persistent infection.

We report here that extracellular TGF-beta 1 is associated exclusively with microfibrils of elastin which are present in the extracellular matrix of the inflamed articular joint of the rat. Inflammation was initiated by bacterial cell walls localized in the synovium following intraperitoneal injection of the bacterial components. This synovitis is associated with both destruction of connective tissue components and matrix deposition. The growth factor was localized by using a polyclonal antibody raised to a synthetic peptide corresponding to amino terminal 30 amino acids of TGF-beta 1 in conjunction with a gold-labeled secondary antibody. The results suggest a close association of TGF-beta 1 with proteoglycans which are known to be a major component of the microfibrils in elastin. Proteoglycan-mediated binding and concentration of TGF-beta 1 in specific areas of the extracellular matrix may constitute a mechanism whereby the growth factor could be targeted to specific sites of action.

Steroids are able to modulate tumor growth. These mechanisms involve probably a complex network of events which earlier were thought to be rather independent of each other. This review summarizes some new results in steroid hormone research, concerning its influence in understanding of tumor growth, above all estrogen dependent mammary tumor growth. It focuses on the following main topics situated in the centre of research at present. 1. Steroid receptors triggering the biological action of steroids are members of a superfamily of transcriptional activators with potential growth modulating properties. The DNA-binding domain of these different proteins is highly conserved. Tumor cells possibly use some of these molecules for their own growth. 2. Hormone dependent mammary tumor growth includes probably a very complex interaction of steroids with their nuclear receptors, growth factors and their membrane receptors, proteolytic enzymes and others. Tumor cells are able to secrete a lot of different proteins in response to estradiol.

Remission rate of 30-50% can be obtained by different cytostatic combinations in second-line-therapy of the metastasized breast cancer. The combination of adriamycin and vincristine with cytostasan reveals a remission rate of 52% in 50 CMF-pretreated female patients. Considerable toxic side effects led to a dose reduction of cytostasan and adriamycin in 31 female patients without clinical efficiency loss. The long remission periods of the total responders (5+ -23 months) are remarkable. Both 3 female patients with bone +/- soft tissue metastasis and 3 female patients with visceral metastasis benefited from a clinical total remission. The remission rates indicated no significant differences between the group of patients with soft tissue +/- bone metastasis (56.3%) and that with a predominantly visceral metastasis (50.0%). The CyAV-combination with a low dose provides an effective therapeutical scheme with acceptable side effects for CMF-pretreated female patients with breast cancer.

Because of its severe side effects, initial clinical trials of the antineoplastic compound mitoguazone (Methyl-GAG, M-G) were ceased in the middle of 1960s. One decade later pharmacokinetically guided dose schedules as well as new experimental data on the antiproliferative mechanism of action stimulated new clinical studies. First results indicated that M-G had single-agent activity against various tumors such as acute leukemia and malignant lymphoma connected with acceptable tolerance. M-G seems to be effective especially in combination with other antineoplastic drugs. Its final evaluation may be reserved to further randomized trials. Recently, the psoriasis vulgaris is expected to be an additional field of the application of M-G. In this minireview data on synthesis, preclinical pharmacology, pharmacokinetics, biochemical effects and toxicology of M-G are given. Furthermore, clinical findings on M-G concerning its pharmacokinetic behaviour, antitumor and antipsoriatic activities are described.

The data presented show no direct correlation between spontaneous tumor incidence and (a) the life span of species, (b) the life span of different strains or stocks of the same species, and (c) the life span of certain populations of the same strain or stock. This conclusion is in conflict with the concept suggesting a summation effect of the events that cause malignant growth irrespective of aging per se, in the age-related increase in cancer incidence, and indicates an important role of age-related changes occurring in the organism in the realization of carcinogenic effect of endogenous and/or exogenous factors.