tretinoin and Fibrosarcoma

Cancer is a major cause of death, and the development of new anticancer drugs is urgently needed. Invasion and metastasis are the primary causes of death due to cancer rather than growth of the primary tumor. In the current study, we examined the anti-invasive effects of p-dodecylaminophenol (1), which was developed based on N-(4-hydroxyphenyl)retinamide (2), a synthetic amide of all-trans-retinoic acid (3). In HT1080 cells 1 inhibited growth, induced apoptosis and arrested the cell cycle in S phase in a dose-dependent manner. In addition, 1 significantly suppressed cell invasion, and the activity and mRNA expression of matrix metalloproteinase-9 (MMP-9). Furthermore, the expression of the reversion-inducing cysteine-rich protein with Kazal motifs (RECK), which is a negative regulator of MMP-9, was increased by treatment with 1. These results suggest that 1 could be an effective anti-cancer agent that suppresses cell growth through apoptosis induction and cell cycle arrest, which also inhibits cell invasion by decreasing MMP-9 expression due to an increase in RECK. Compound 1 might be useful clinically as a new and potent anticancer agent that could overcome adverse side effects of the retinoids.

Topics: Aminophenols; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Fibrosarcoma; Humans; Molecular Structure; Neoplasm Invasiveness

The highly aggressive adult sarcomas are characterized by high levels of matrix metalloproteinase (MMP)-2 and -9, which play crucial roles in tumor invasion and metastasis by degradation of the extracellular membrane leading to cancer cell spread to distal organs. We examined the effect of cytokines, mitogens, inducers and inhibitors on MMP-2 and MMP-9 secretion in chondrosarcoma (SW-1353), fibrosarcoma (HT-1080), liposarcoma (SW-872) and synovial sarcoma (SW-982) cell lines. The selected compounds included natural cytokines and growth factors, as well as chemical compounds applied in therapy of sarcoma and natural compounds that have demonstrated anticancer therapeutic potential. MMP-2 and MMP-9 secretions were analyzed by gelatinase zymography following 24-h exposure to the tested agents and quantitated by densitometry. Fibrosarcoma, chondrosarcoma, liposarcoma and synovial sarcoma showed bands corresponding to MMP-2 and MMP-9 with dose-dependent enhancement of MMP-9 with phorbol 12-myristate 13-acetate (PMA) treatment. In chondrosarcoma cells, tumor necrosis factor (TNF)-α had a stimulatory effect on MMP-9 and insignificant effect on MMP-2 and interleukin (IL)-1β stimulated MMP-9 and MMP-2. In fibrosarcoma and liposarcoma cells, TNF-α had a profound stimulatory effect on MMP-9, but no effect on MMP-2 and in synovial sarcoma an inhibitory effect on MMP-2 and no effect on MMP-9. IL-1β had a slight inhibitory effect on fibrosarcoma, liposarcoma and synovial sarcoma MMP-2 and MMP-9 except for MMP-9 in synovial sarcoma which showed slight stimulation. Lipopolysaccharide (LPS) stimulated expression of MMP-2 in fibrosarcoma and chondrosarcoma while inhibited it in liposarcoma. Doxycycline, epigallocatechin gallate and the nutrient mixture inhibited MMP-2 and MMP-9 in all cell lines. Actinomycin-D, cyclohexamide, retinoic acid, and dexamethasone inhibited MMP-2 and -9 in chondrosarcoma and fibrosarcoma cells. Our results show that cytokines, mitogens, inducers and inhibitors have an up or down regulatory effect on MMP-2 and MMP-9 expression in adult sarcoma cell lines, suggesting these agents may be effective strategies to treat these cancers.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Carcinogens; Catechin; Cell Line, Tumor; Chondrosarcoma; Dactinomycin; Dexamethasone; Doxycycline; Fibrosarcoma; Humans; Interleukin-1beta; Lipopolysaccharides; Liposarcoma; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Sarcoma; Sarcoma, Synovial; Tetradecanoylphorbol Acetate; Tretinoin; Tumor Necrosis Factor-alpha

The expression of the Adenovirus serotype 5 (Ad5) E1A oncogene sensitizes tumor cells to natural killer (NK) cell-mediated killing and tumor rejection in vivo. These effects are dependent on the ability of E1A to bind the transcriptional coadaptor protein p300. To test the hypothesis that E1A up-regulates ligands recognized by the NKG2D-activating receptor, we stably transfected the highly tumorigenic mouse fibrosarcoma cell line MCA-205 with Ad5-E1A or a mutant form of E1A that does not interact with p300 (E1A-Deltap300). Ad5-E1A, but not E1A-Deltap300, up-regulated the expression of the NKG2D ligand retinoic acid early inducible (RAE)-1, but not murine ULBP-like transcript 1, another NKG2D ligand, in four independently derived MCA-205 transfectants. The up-regulation of RAE-1 by E1A targeted MCA-205 tumor cells to lysis by NK cells, resulting in NKG2D-dependent tumor rejection in vivo. Moreover, the up-regulation of NKG2D ligands by E1A was not limited to mouse tumor cells, as E1A also increased the expression of NKG2D ligands on primary baby mouse kidney cells, human MB435S breast cancer cells, and human H4 fibrosarcoma cells.

Topics: Adenoviridae; Adenovirus E1A Proteins; Animals; Antineoplastic Agents; Cell Line, Tumor; E1A-Associated p300 Protein; Fibrosarcoma; Genetic Vectors; Graft Rejection; Humans; Kidney; Killer Cells, Natural; Mice; Neoplasm Transplantation; Neoplasms, Experimental; NK Cell Lectin-Like Receptor Subfamily K; Promoter Regions, Genetic; Receptors, Immunologic; Receptors, Natural Killer Cell; Tretinoin; Up-Regulation

Tumor-induced immunosuppression is one of the crucial mechanisms of tumor evasion of immune surveillance. It contributes greatly to the failure of cancer vaccines. Immature myeloid cells (ImCs) play an important role in tumor-induced immunosuppression. These cells accumulate in large numbers in tumor-bearing hosts and directly inhibit T-cell functions via various mechanisms. In this study, we tried to eliminate ImCs in an attempt to improve antitumor response. In vivo administration of all-trans-retinoic acid (ATRA) dramatically reduced the presence of ImCs in all tested tumor models. This effect was not because of a direct antitumor effect of ATRA or decreased production of growth factors by tumor cells. Experiments with adoptive transfer demonstrated that ATRA differentiated ImC in vivo into mature dendritic cells, macrophages, and granulocytes. Decreased presence of ImC in tumor-bearing mice noticeably improved CD4- and CD8-mediated tumor-specific immune response. Combination of ATRA with two different types of cancer vaccines in two different tumor models significantly prolonged the antitumor effect of the treatment. These data suggest that elimination of ImC with ATRA may open an opportunity to improve the effect of cancer vaccines.

Topics: Adenocarcinoma; Adoptive Transfer; Animals; Cancer Vaccines; CD4-Positive T-Lymphocytes; Cell Differentiation; Drug Synergism; Female; Fibrosarcoma; Immune Tolerance; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Myeloid Cells; Tretinoin

Exposure of human tumor cell lines to different chemotherapeutic drugs, ionizing radiation, and differentiating agents induced morphological, enzymatic, and ploidy changes resembling replicative senescence of normal cells. Moderate doses of doxorubicin induced this senescence-like phenotype (SLP) in 11 of 14 tested cell lines derived from different types of human solid tumors, including all of the lines with wild-type p53 and half of p53-mutated cell lines. SLP induction seemed to be independent from mitotic cell death, the other major effect of drug treatment. Among cells that survived drug exposure, SLP markers distinguished those cells that became terminally growth-arrested within a small number of cell divisions from the cells that recovered and resumed proliferation. SLP induction in breast carcinoma cells treated with retinoids in vitro or in vivo was found to correlate with permanent growth inhibition under the conditions of minimal cytotoxicity, suggesting that this response may be particularly important for the antiproliferative effect of differentiating agents. The senescence-like program of terminal proliferation arrest may provide an important determinant of treatment outcome and a target for augmentation in cancer therapy.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Division; Cellular Senescence; Doxorubicin; Female; Fibrosarcoma; Gamma Rays; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Neoplastic Stem Cells; Phenotype; Ploidies; Tretinoin; Tumor Cells, Cultured

Transcription of the human tissue-type plasminogen activator (t-PA) gene is regulated by a multi-hormonal responsive enhancer at -7 kb. Transient co-transfections of Drosophila SL2 and human HT1080 fibrosarcoma cells with t-PA reporter constructs showed that Sp1 and Sp3 activate the t-PA promoter. Moreover Sp1 (but not Sp3) binding to the promoter is involved in induction by retinoic acid (RA), a response mediated through the enhancer. The role of Sp1 is specific, since mutation of the CRE element in the promoter did not affect response to RA. In contrast, the glucocorticoid induction mediated by the enhancer is independent of these Sp1 and CRE elements.

Topics: Animals; Binding Sites; Cells, Cultured; Dexamethasone; DNA-Binding Proteins; Drosophila; Fibrosarcoma; Humans; Promoter Regions, Genetic; Recombinant Proteins; Sp1 Transcription Factor; Sp3 Transcription Factor; Tissue Plasminogen Activator; Transcription Factors; Transcription, Genetic; Transfection; Tretinoin

The ret finger protein (rfp) is a member of the B-box zinc finger gene family many of which may function in growth regulation and in the appropriate context become oncogenic. Members of this family are nuclear proteins that possess a characteristic tripartite motif consisting of the RING and B-box zinc binding domains and a coiled-coil domain. The promyelocytic leukemia gene (PML), another B-box family member, produces a protein product that is detected within punctate nuclear structures called PML nuclear bodies (NBs) or PML oncogenic domains (PODs). These NBs are complex structures that consist of a number of different proteins many of which have yet to be identified. In the disease acute promyelocytic leukemia (APL) a fusion protein, PML-RARA, is produced through the t(15:17) translocation. In APL the morphology of the NBs is altered. We report that rfp co-localizes with PML in a subset of the PML NBs and that it interacts directly with PML. This interaction is mediated through the rfp B-box and the distal two coils. In contrast, homomultimerization of rfp preferentially involves the B-box and the proximal coil. The association of rfp with the PML NBs is altered by mutations that affect rfp/PML interaction and in NB4 cells that are derived from APL patients. When treated with retinoic acid, rfp reassociates with the NBs in a pattern similar to non APL cells. Additionally, we found that rfp colocalizes with PML-RARA protein produced in APL patients. These results suggest that rfp, along with the other known/unknown components of PML NBs, have an important role in regulating cellular growth and differentiation.

Topics: Amino Acid Sequence; Antineoplastic Agents; Cell Differentiation; Cell Division; Cell Nucleus; DNA-Binding Proteins; Fibrosarcoma; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Promyelocytic, Acute; Molecular Sequence Data; Mutagenesis; Neoplasm Proteins; Nuclear Proteins; Promyelocytic Leukemia Protein; Protein Binding; Recombinant Proteins; Transcription Factors; Transfection; Tretinoin; Tumor Cells, Cultured; Tumor Suppressor Proteins; Zinc Fingers

Retinoids have shown great promise as chemopreventive against the development of squamous cell carcinomas of the upper aerodigestive tract. However, the exact mechanism by which they block new tumors from arising is unknown. Here, we report that 13-cis- and all-trans-retinoic acid, used at clinically achievable doses of 10(-6) mol/L or less, can directly and specifically affect cell lines cultured from oral squamous cell carcinomas, inducing them to switch from an angiogenic to an anti-angiogenic phenotype. Although retinoic-acid-treated and untreated tumor cells make the same amount of interleukin-8, the major inducer of neovascularization produced by such tumor lines, they vary in production of inhibitory activity. Only the retinoic-acid-treated cells produce a potent angio-inhibitory activity that is able to block in vitro migration of endothelial cells toward tumor cell conditioned media and to halt neovascularization induced by such media in the rat cornea. Anti-angiogenic activity is induced in the tumor cells by low doses of retinoids in the absence of toxicity with a kinetics that suggest that it could be contributing to the effectiveness of the retinoids as chemopreventive agents.

Topics: Animals; Breast Neoplasms; Carcinoma, Squamous Cell; Colonic Neoplasms; Cornea; Endothelium, Vascular; Female; Fibrosarcoma; Humans; Interleukin-8; Keratinocytes; Neovascularization, Pathologic; Neovascularization, Physiologic; Neutralization Tests; Phenotype; Rats; Rats, Inbred F344; Tongue Neoplasms; Transforming Growth Factor beta; Tretinoin; Tumor Cells, Cultured

We have created fusion proteins between Fas and the ligand-binding domain of the estrogen or retinoic acid receptor. Murine fibrosarcoma L929 cells and human cervical carcinoma HeLa cells expressing the fusion proteins demonstrated apoptotic phenotypes in a tightly estrogen- or retinoic acid-dependent manner in vitro. Moreover, the fusion protein-expressing L929 cells transplanted into nude mice were also killed through apoptosis after injection of an estrogen agonist. This represents a novel system, "cell targeting," that can eliminate cells not only in vitro but also in vivo through the activation of a natural suicide machinery, i.e., apoptosis, by currently used hormones. This system implies wide applications not only in developmental biology and neurobiology but also in medicine, especially for cancer gene therapy.

Topics: Amino Acid Sequence; Animals; Apoptosis; Cell Line; Cell Nucleus; Chlorocebus aethiops; Estradiol; Estriol; fas Receptor; Female; Fibrosarcoma; HeLa Cells; Humans; Male; Mice; Mice, Nude; Molecular Sequence Data; Receptors, Estrogen; Recombinant Fusion Proteins; Sequence Tagged Sites; Tamoxifen; Transfection; Tretinoin; Tumor Cells, Cultured; Uterine Cervical Neoplasms

All-trans-retinoic acid (RA) and retinoids induce synthesis of tissue-type plasminogen activator (t-PA) in endothelial and neuroblastoma cells in vitro and in rats in vivo. In HT1080 fibrosarcoma cells, induction of t-PA-related antigen secretion and t-PA mRNA steady state levels by RA were found to depend on de novo protein and mRNA synthesis. Fragments derived from the 5'-flanking region of the t-PA gene (+197 to -9578 base pairs (bp)) were linked to the chloramphenicol acetyltransferase gene. Transfection studies demonstrated that the region spanning bp -7145 to -9578 mediated induction by RA. A functional retinoic acid response element (RARE), consisting of a direct repeat of the GGGTCA motif spaced by 5 nucleotides (t-PA/DR5), was localized at -7.3 kilobases. The t-PA/DR5 element interacted with the heterodimer composed of retinoic acid receptor alpha and retinoid X receptor alpha in vitro, whereas its mutation abolished induction by RA in transient expression. In human EA.hy926 hybrid endothelial and in SK-N-SH neuroblastoma cells, the activity of t-PA/DR5 was found to be independent of the intervening sequence (-632 to -7144 bp) and of its distance from the transcription initiation site. Staurosporine, an inhibitor of protein kinase activity, inhibited induction by RA, suggesting that it required protein phosphorylation.

Topics: Alkaloids; Animals; Base Sequence; Cell Line; Chloramphenicol O-Acetyltransferase; DNA; Dose-Response Relationship, Drug; Endothelium; Enzyme Induction; Fibrosarcoma; Gene Expression; Gene Expression Regulation, Enzymologic; Humans; Molecular Sequence Data; Mutagenesis; Neuroblastoma; Oligodeoxyribonucleotides; Protein Kinase C; Protein Multimerization; Rats; Receptors, Retinoic Acid; Recombinant Proteins; Repetitive Sequences, Nucleic Acid; Retinoic Acid Receptor alpha; Retinoid X Receptors; Sequence Deletion; Staurosporine; Tissue Plasminogen Activator; Transcription Factors; Transfection; Tretinoin; Tumor Cells, Cultured

The importance of cell-associated plasminogen activation in the extracellular matrix degradation processes is becoming increasingly evident. To elucidate the modulators of net plasminogen activation on the cell surface, we have recently established an assay system. Using this system, we examined the effects of several candidate modulators on cell surface plasminogen activator in the human fibrosarcoma cell line HT-1080 and the SV40-transformed human lung fibroblast cell line WI-38 VA 13 2RA. Although the majority of the candidates had no effect or a selective effect on either cell line, only retinoic acid markedly enhanced cell surface plasminogen activator activity in both HT-1080 and WI-38 VA13 2RA cells in a time-dependent manner. The effect of retinoic acid was neutralized by actinomycin D. The enhanced activity was inhibited by anti-uPA IgG and by pretreatment with phosphatidylinositol-specific phospholipase C. These findings suggest that retinoic acid increases the amount of receptor-bound uPA via de novo synthesis, and that it plays an important role in modulating cell-associated plasminogen activation.

Topics: Cell Line, Transformed; Cell Membrane; Fibroblasts; Fibrosarcoma; Humans; Lung Neoplasms; Plasminogen; Tretinoin; Tumor Cells, Cultured

The human myeloid leukemia cell lines HL-60, U-937, and THP-1 were used to analyze the alterations of transforming growth factor beta (TGF-beta) during hematopoietic cell growth and differentiation. Differentiation of these cell lines was induced by the phorbol ester phorbol 12-myristate 13-acetate, tumor necrosis factor alpha or by retinoic acid. Northern hybridization analyses indicated that the basal levels of TGF-beta 1, latent TGF-beta binding protein, and type II TGF-beta receptor (T beta IIR) mRNAs were low in untreated cells. Major increases of these mRNAs were observed in cells treated with phorbol 12-myristate 13-acetate, with maximal induction after 12-72 h of stimulation. Retinoic acid and tumor necrosis factor alpha elevated significantly only the expression of T beta IIR mRNA. TGF-beta 1 induced its receptor mRNA in HL-60 and U937-1SF cells but not in THP-1 cells. These changes in gene expression were related to the differentiation of myeloid leukemia cells. Affinity labeling with 125I-TGF-beta 1 indicated that type I TGF-beta receptor was coregulated with T beta IIR. Types I and II receptors were coprecipitated by T beta IIR-specific antibodies. Differentiation of myeloid cells induced secretion of latent TGF-beta 1 protein, as shown by immunoblotting, but significant changes in the levels of active TGF-beta were not observed. These results indicate that the genes involved in TGF-beta signal transduction are coordinately up-regulated during myeloid differentiation.

Topics: Amino Acid Sequence; Animals; Antibodies; Base Sequence; Cell Differentiation; Cell Line; Cloning, Molecular; DNA Primers; Fibrosarcoma; Gene Expression; Humans; Kinetics; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Lung; Mink; Molecular Sequence Data; Polymerase Chain Reaction; Receptors, Transforming Growth Factor beta; Recombinant Fusion Proteins; RNA, Messenger; Tetradecanoylphorbol Acetate; Time Factors; Transforming Growth Factor beta; Tretinoin; Tumor Cells, Cultured

We investigated the mechanism by which retinoic acid causes growth arrest and flat reversion of SSV-NRK, simian sarcoma virus-transformed normal rat kidney cells. Northern analysis revealed that both chronic (7 days) and acute (6 h) retinoic acid treatment of serum-stimulated SSV-NRK cells caused a 6-fold decrease in c-fos mRNA levels. In addition, nuclear run-on experiments showed that retinoic acid regulated c-fos expression in SSV-NRK cells at the transcriptional initiation level. Attenuation of c-fos transcription was equal in both retinoic acid-treated and control cells, and no increased c-fos mRNA turnover was detected in retinoic acid-treated cells. Furthermore, there was no observed change in the c-fos mRNA levels after only 30 min of retinoic acid treatment, suggesting that a mechanism involving the interruption of the signal transduction mechanism at the membrane level is unlikely. Because it has been shown that c-fos expression plays a pivotal role in mitogenesis of quiescent fibroblasts, we conclude that the retinoic acid-mediated down-regulation of c-fos expression is a mechanism for growth inhibition in SSV-NRK cells.

Topics: Animals; Cell Division; Cycloheximide; Down-Regulation; Fibrosarcoma; Gene Expression Regulation, Neoplastic; Genes, fos; Half-Life; RNA, Messenger; Signal Transduction; Transcription, Genetic; Tretinoin; Tumor Cells, Cultured

The effects of various retinoids and dexamethasone on protein and type IV collagen synthesis were studied in human basement membrane-forming fibrosarcoma (HT-1080) cells. Retinol, etretinate (Ro-10-9359), free acid of etretinate (Ro-10-1670) and 13-cis-retinoic acid (RA) in 10(-7) M concentrations slightly reduced total protein and type IV collagen synthesis in the HT-1080 cells, the largest decrease being found with Ro-10-1670 and 13-cis-RA. In contrast, dexamethasone markedly stimulated the incorporation of [14C]proline and the synthesis of [14C]hydroxyproline, an index of the synthesis of type IV collagen. Part of the increase noted in total protein synthesis and type IV collagen synthesis after dexamethasone was due to enhanced intracellular activity of proline. Retinoids did not markedly affect the specific activity of proline. The addition of 13-cis-RA with dexamethasone also increased total protein and type IV collagen synthesis, but to a lesser extent than did dexamethasone alone. 13-cis-RA did not affect the synthesis of fibronectin, a component of connective tissue matrix, while dexamethasone clearly increased the absolute and relative synthesis of fibronectin. Thus the results indicate that retinoids modulate the metabolism of HT-1080 cells, in a way which is separate from that of glucocorticoids. It is also possible that retinoids used in vivo in clinical practice may modulate the metabolism of the connective tissue matrix of basement membranes, i.e. type IV collagen.

Topics: Acitretin; Collagen; Dexamethasone; Electrophoresis, Starch Gel; Etretinate; Fibronectins; Fibrosarcoma; Isotretinoin; Retinoids; Tretinoin; Tumor Cells, Cultured; Vitamin A

Topics: Animals; Cell Adhesion; Cell Division; Cell Line; Clone Cells; Female; Fibrinolysis; Fibrosarcoma; HeLa Cells; Humans; Melanoma; Mice; Neoplasms; Osteosarcoma; Plasminogen Activators; Tretinoin; Vulvar Neoplasms

The effect of 200 micrograms doses of all-trans retinoic acid, given over a long duration (daily for 8 weeks, suspended for 3 weeks, then resumed daily for 4 weeks) or short duration (daily for 30 days), on the induction of fibrosarcomas in C57BL/6J mice by MCA was evaluated. A reduced level of carcinogenesis was observed with both lengths of retinoic acid treatment, since respective incidences of MCA fibrosarcomas were 63 and 61% of those in saline-treated controls. In other studies, the effect of all-trans retinoic acid on syngeneic growth of two experimental fibrosarcomas (B6 25 and B6 27, induced previously in C57BL/6J mice by MCA) was assessed. Retinoic-acid-treated mice were more resistant to higher doses of viable B6 27 (LD50 = 2.85) and especially B6 25 (LD50 = 3.80) than were corresponding saline- or corn-oil-treated controls (LD50 less than 2.0). The strength of resistance conferred by retinoic acid treatment thus varied considerably between these tumors, despite their common strain derivation and histopathological origin. Additional studies explored the effect on B6 27 growth of giving all-trans retinoic acid during either the sensitization or challenge stage of standard syngeneic immunogenicity tests. Mice given all-trans retinoic acid during sensitization displayed a markedly increased resistance to challenge with the immunospecific B6 27 tumor (LD50 = 5.30), compared to challenged controls that received saline (LD50 = 2.60) or corn-oil (LD50 = 2.55) during preimmunization. In contrast, when B6 27-preimmunized mice were treated with all-trans retinoic acid after challenge with homologous tumor, resistance to B6 27 (assessed by tumor growth rate and LD50 dose) was not increased but remained comparable to that of saline-or corn-oil-treated controls. While the mechanism(s) by which all-trans retinoic acid inhibits syngeneic growth of MCA tumors is unknown, our results support an immunostimulatory effect, evidenced by tumor resistance in both non-immune and specifically preimmunized syngeneic hosts.

Topics: Animals; Female; Fibrosarcoma; Immunity; Lethal Dose 50; Methylcholanthrene; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Sarcoma, Experimental; Tretinoin

After subcutaneous application of 0.5 mg 3,4-benzopyrene (BP) to Sprague-Dawley-rats on the 2nd day of life, 50% of the animals developed local fibrosarcomas after 250 +/- 70 days. Additional treatment with immunostimulating (BCG, albumin, vitamin A-acid) or immunodepressive agents (hydrocortisone, cyclophosphamide, methotrexat) which was started 6 days after birth and maintained throughout life, did not influence carcinogenesis with respect to tumor incidences and induction periods of tumors.

Topics: Animals; BCG Vaccine; Benzopyrenes; Female; Fibrosarcoma; Immunosuppressive Agents; Male; Neoplasms, Experimental; Rats; Serum Albumin; Tretinoin