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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retinoids alone and in combination with interferon-alpha are the best systemic agents to study in the reversal of skin carcinogenesis and in the treatment of advanced squamous cell carcinoma of the skin. This article reviews the major laboratory advances in the mechanistic study of retinoids and interferons alone and in combination. Recent data in several cancer cell lines suggest that retinoic acid can potentiate the interferon signal-transduction pathway. Also reviewed is the current status of clinical studies of systemic retinoids and interferon in (i) skin cancer prevention (as single agents) and (ii) treatment of advanced squamous cell carcinoma (as single agents and in combination). Future clinical studies with translational laboratory correlates are necessary to determine the roles of retinoids and interferons in the prevention and treatment of skin cancer.
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PMID:Retinoids and interferons in non-melanoma skin cancer. 962 20

Nitric oxide (NO), an endogenous free radical, has been implicated in a wide range of biological functions. NO is generated enzymatically from the terminal guanidinonitrogen of L-arginine by nitric oxide synthase (NOS). Despite intensive investigations, the role of NO--either as the primary product of the L-arginine/NOS pathway or provided from the NO donor sodium nitroprusside (SNP)--in carcinogenesis and tumour cell growth remains unclear and controversial. The objective of this study was to examine the growth effects of NO on a ductal pancreatic adenocarcinoma in the rat and on a human pancreatic tumour cell line (HA-hpc2). In vivo, both SNP and endogenous induction of NO by endotoxins [lipopolysaccharide (LPS)] plus L-arginine significantly reduced the tumour growth. To investigate the mechanisms of NO anti-tumour growth action, the effects of either the SNP or L-arginine/NOS pathway were analysed on the HA-hpc2 cell line. Nitrite/nitrate production, NOS activity and iNOS expression [assessed by reverse transcription-polymerase chain reaction (RT-PCR)] were tested and related to growth (assessed by [3H]thymidine incorporation assay) and apoptosis (assessed by internucleosomal DNA cleavage). SNP exerted a dual effect on tumour cells: stimulation of the proliferation up to 1 mM and inhibition at higher concentrations. These effects were related to NO production. Both proliferative and cytostatic responses were inhibited by NO scavenger 2-phenyl-4,4,5,5-tetramethyl-hemidazoline-1-oxyl3-oxide (carboxy-PTIO). The marked apoptotic DNA fragmentation induced by SNP was also abolished by PTIO association. Unlike macrophages, the human pancreatic tumour cells did not seem to express intrinsically the L-arginine/NOS pathway. Macrophages were activated by HA-hpc2 cells as well as by LPS plus cytokines [interleukin (IL)-1beta plus tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma]. In HA-hpc2/macrophage co-cultures, NOS activity and inducible NOS (iNOS) transcription were stimulated, whereas an antiproliferative response was observed. These effects were related to both macrophage amount and NO production. Addition of LPS plus cytokines to co-cultures doubled iNOS activity, nitrite/nitrate production and tumoricidal effect. These data suggest the involvement of NO in pancreatic tumour growth and support the fact that generation of high levels of NO with potential production of endogenous reactive nitrogen intermediates may contribute to induction of apoptosis and tumour growth inhibition.
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PMID:Role of nitric oxide in pancreatic tumour growth: in vivo and in vitro studies. 976 73

The activity of interferon (IFN) is not elucidated from the viewpoint of cancer prevention in chronic hepatitis C patients en masse. The hepatocellular carcinogenesis rate was analyzed statistically in 1,643 patients with chronic hepatitis C: 1,191 patients with IFN therapy and 452 without IFN therapy. Hepatocellular carcinogenesis rates in the treated and untreated groups were 2.1% and 4.8% at the end of the 5th year, and 7.6% and 12.4% at the 10th year, respectively (P =.0036). Multivariate analysis showed that IFN slightly decreased the risk of carcinogenesis by 33%, compared with that of untreated patients (P =. 14), adjusting for the confounding effects of age, fibrotic stage, gender, and gamma-glutamyl transpeptidase (GGTP) value. Among 1,191 patients with IFN, 461 patients attained persistent loss of hepatitis C virus (HCV) RNA, and the other 145 patients retained normal alanine transaminase (ALT) values without loss of HCV RNA. The hazard of carcinogenesis in these 606 patients with persistent normal ALT with or without HCV-RNA clearance was significantly lower than that of untreated patients (hazard ratio: 0.32; P =.012) and that of the abnormal aminotransferase group. Among patients with chronic hepatitis C, IFN significantly decreased the hepatocellular carcinogenesis rate in those patients with normal or persistent low ALT values.
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PMID:Effect of interferon therapy on hepatocellular carcinogenesis in patients with chronic hepatitis type C: A long-term observation study of 1,643 patients using statistical bias correction with proportional hazard analysis. 1009 56

The modifying effects of auraptene isolated from the peel of citrus fruit (Citrus natsudaidai Hayata) on macrophage and lymphocyte functions were investigated in mice. Female BALB/c mice were gavaged with auraptene at a dose of 100, 200 or 400 mg/kg once a day for 10 consecutive days. Glucose consumption of peritoneal macrophages was significantly higher than that in the control group (P < 0.05-0.001) in auraptene-treated mice at all doses at 24, 48 and 72 h incubation except for mice given 200 mg/kg auraptene at 24 h incubation. Activity of acid phosphatase in peritoneal macrophages was significantly increased in mice treated with auraptene at a dose level of 100 mg/kg (P < 0.001). Activity of beta-glucuronidase in peritoneal macrophages in the auraptene-treated mice at all doses was significantly higher than that in the control group (P < 0.001), but there was no significant difference in lactate dehydrogenase activity of peritoneal macrophages at any dose. Interleukin (IL)-1beta production of peritoneal macrophages in the auraptene-treated mice at all doses was significantly higher than that in the control group (P < 0.05-0.001). Tumor necrosis factor alpha production of peritoneal macrophages in mice gavaged with auraptene at a dose of 200 mg/kg was significantly higher than that in the control group (P < 0.05). Auraptene did not affect proliferation of spontaneous splenic lymphocytes in mice at any dose. Stimulation indices in mice given auraptene at a dose of 200 mg/kg were significantly higher than that in the control group (P < 0.05). When spleenic lymphocytes were cultured without concanavalin A (Con A), IL-2 and interferon (IFN) gamma productions were not detectable in the supernatant. However, IL-2 and IFN production stimulated by Con A were significantly increased in mice gavaged with auraptene at dose levels of 100 and 200 mg/kg (P 0.05-0.001). Auraptene did not enhance spontaneous IL-4 production by splenocytes. There was no significant difference in IL-4 production of splenic lymphocytes stimulated by Con A in all groups. These findings might suggest that oral administration of citrus auraptene effectively enhanced macrophage and lymphocyte functions in mice.
Carcinogenesis 1999 Aug
PMID:Immunomodulatory action of citrus auraptene on macrophage functions and cytokine production of lymphocytes in female BALB/c mice. 1042 94

In this review, we aim to synthesize the emerging picture of retinoids in lung cancer through a summary of ongoing investigations in biology, chemoprevention and therapy settings, in an attempt to clarify the possible role of these agents in such a disease. Early work in head and neck cancer has evidenced the capability of retinoids to interrupt field carcinogenesis by reversing premalignant lesions and decreasing the incidence of second primary tumors (SPTs). At this time, the completed randomized trials in lung cancer have failed to demonstrate an evident chemopreventive effect of the tested agents on different study end points, although both a marginally significant benefit of retinol palmitate in time-to-development rates for smoke-related SPTs and a potential preventive effect of retinol supplementation against mesothelioma in selected populations of asbestos-exposed workers have been recently reported. Concerning the role of retinoids in lung cancer treatment, a moderate activity of 13-cis-retinoic acid (13cRA) or all-transretinoic acid (ATRA) as single agents has been reported in small series of advanced, mostly pretreated lung cancer patients. More encouraging findings derive from combination studies, in which retinoids, especially ATRA, are added to either alpha-interferon or chemotherapy and radiotherapy. Major recent advances have been made towards the understanding of retinoids mechanisms of action; at this regard, the role of RAR-beta basal or treatment-induced levels seems to be of particular interest as intermediate end point and/or independent prognostic factor, besides their known importance in lung carcinogenesis. Future research for chemopreventive and therapeutic programs with retinoids in lung cancer should be focused on the investigation of new generation compounds with a specificity for individual retinoid nuclear receptors. Such selective molecules may have a greater activity against lung cancer, with a more favourable toxicity profile, as recently suggested by our preliminary data on Ro 41-5253.
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PMID:Retinoids in lung cancer chemoprevention and treatment. 1058 49

The known mechanisms of hepatitis C virus (HCV) clearance and their failure in persistent infection are discussed. Interferon-alpha is the main treatment in chronic HCV but has shown poor sustained virological response rates when used as a monotherapy. The effects of interferon-a may include inhibition of HCV virion production by an effect on viral RNA and protein synthesis, enhancement of immune lysis of HCV infected cells, inhibition of hepatic fibrosis by an effect on TGFbeta, and an effect on HCV induced carcinogenesis. Mathematical modelling studies have provided insights into the mechanisms of action of interferon-alpha in chronic HCV. The two-phase plasma HCV RNA disappearance curve may reflect the presence of an interferon-resistant second site of HCV replication either within or outside the liver. Clinical observations and cerebral magnetic resonance scans provide evidence of functional cerebral impairment in HCV infected patients, raising the issue of the central nervous system (CNS) as a site for HCV replication. Recent studies using ribavirin in combination with interferon suggest that this approach doubles the sustained response rates obtained without having a major effect on the initial rate of HCV clearance (see Zeuzem paper). The potential mechanisms of action of ribavirin, although not yet fully understood, include inhibition of synthesis of GTP by an effect on inosine monophosphate dehydrogenase thereby limiting viral RNA synthesis, and enhancement of TH1 responses, which may assist viral clearance. There is no significant effect on HCV RNA polymerase activity. It is possible that ribavirin may have activity at extrahepatic sites of HCV infection, thus explaining the marked reduction in relapse rates with combination therapy, without an appreciable effect on initial antiviral response.
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PMID:Possible mechanisms of action and reasons for failure of antiviral therapy in chronic hepatitis C. 1062 79

The effect of a synthetic interferon inductor Cycloferone on colon carcinogenesis was firstly studied in rats. Seventy-five 2-month-old outbred female LIO rats were subdivided into three groups and were weekly exposed to 15 s.c. injections of 1,2-dimethylhydrazine (DMH) at a single dose of 7 mg/kg body wt. From the day of the fist injection of DMH rats from group 2 were given weekly i.p. injections of Cycloferone (62.5 mg/kg) until the end of the experiment. DMH-treated rats (group 3) were exposed to weekly i.p. injections of Cycloferone (62.5 mg/kg) starting in the week after the last injection of the carcinogen. Rats from group 1 were exposed to DMH and treated weekly with 0.2 ml i.p. of normal saline. Additional groups of rats were treated weekly with Cycloferone (62.5 mg/kg) or with 0.2 ml of saline. The experiment was ended 6 months after the first injection of DMH. In DMH-treated rats (groups 1, 2 and 3) colon adenocarcinomas developed in 87, 61 and 59%, respectively. The number of colon tumors per tumor-bearing rat was 2.5, 1.9 and 1.3 in groups 1, 2 and 3, respectively. Treatment with Cycloferone significantly inhibits carcinogenesis in ascending and descending colon. The incidence of tumors of the rectum was decreased in the group 2 as compared with the group 1. There were no cases of tumors of rectum in rats from group 3. The treatment with Cycloferone alone as well as with normal saline failed to induce any tumors in rats. Thus, our results demonstrated inhibitory effect of Cycloferone on colon carcinogenesis induced by DMH in rats.
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PMID:Inhibitory effect of synthetic interferon inductor Cycloferone on 1,2-dimethylhydrazine-induced colon carcinogenesis in rats. 1069 99

In studying biological roles of interferon regulatory factor (IRF)-1 tumor suppressor in cervical carcinogenesis, we found that HPV E7 is functionally associated with IRF-1. Binding assays indicate a physical interaction between IRF-1 and HPV E7 in vivo and in vitro. The carboxyl-terminal transactivation domain of IRF-1 was required for the interaction. Transient co-expression of E7 significantly inhibits the IRF-1-mediated activation of IFN-beta promoter in NIH-3T3 cells. Co-transfection of E7 mutants reveals that the pRb-binding portion of E7 is necessary for the E7-mediated inactivation of IRF-1. It was next determined whether histone deacetylase (HDAC) is involved in the inactivation mechanism as recently suggested, where the carboxyl-terminal zinc finger domain of E7 associates with NURD complex containing HDAC. When trichostatin A, an inhibitor of HDAC, was treated, the repressing activity of E7 was released in a dose-dependent manner. Furthermore, the mutation of zinc finger abrogates such activity without effect on the interaction with IRF-1. These results suggest that HPV E7 interferes with the transactivation function of IRF-1 by recruiting HDAC to the promoter. The immune-promoting role of IRF-1 evokes the idea that our novel finding might be important for the elucidation of the E7-mediated immune evading mechanism that is frequently found in cervical cancer.
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PMID:Inactivation of interferon regulatory factor-1 tumor suppressor protein by HPV E7 oncoprotein. Implication for the E7-mediated immune evasion mechanism in cervical carcinogenesis. 1070 32

Transforming growth factor beta (TGF-beta) plays important roles in the regulation of proliferation, differentiation, apoptosis, and carcinogenesis. To identify genes responsible for maintaining the phenotype induced by TGF-beta, we performed a retrovirus-mediated gene trap screening designed to isolate TGF-beta-responsive genes in human lung carcinoma cell line A549. After screening 249 trap lines, 21 were found to express the reporter beta-galactosidase gene in a TGF-beta-responsive manner. Interestingly, in large proportions of these trap lines, the reporter gene was responsive also to phorbol ester and was suppressed by gamma interferon. Fragments of all these trapped genes were recovered by 5'- and 3'-rapid amplification of cDNA ends (RACE), and in 15 out of 21 cases (71%), the TGF-beta responsiveness of the endogenous genes was confirmed by RNA blot hybridization. In at least five cases, the TGF-beta-induced upregulation was found to be cycloheximide resistant, suggesting the roles of the genes in the TGF-beta-induced primary responses. Sequence analyses revealed that 43% (9 of 21) of the trapped genes were novel and that the remainder included genes previously reported to be upregulated by TGF-beta, such as epidermal growth factor receptor and beta1 integrin, documenting the validity of this approach. Other known genes include the ones encoding the proteins associated with cell proliferation (ribosomal proteins S15a, hNRP/NAP-1, and lipocortin II), focal adhesions (paxillin), and transcriptional regulation (thyroid hormone receptor activator molecule 1 [TRAM-1]).
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PMID:Identification of a series of transforming growth factor beta-responsive genes by retrovirus-mediated gene trap screening. 1075 10

The modifying effects of dietary feeding of a polyisoprenylated benzophenone, garcinol, isolated from Garcinia indica fruit rind on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were investigated in male F344 rats. We also assessed the effects of garcinol on proliferating cell nuclear antigen (PCNA) index in ACF and activities of detoxifying enzymes of glutathione S-transferase (GST) and quinone reductase (QR) in liver. In addition, we examined the effects of garcinol on 12-O-tetradecanoylphorbol-13-acetate-induced O(2)(-) generation in differentiated human promyelocytic HL-60 cells and lipopolysaccharide (LPS)- and interferon (IFN)-gamma-induced nitric oxide (NO) generation in mouse macrophage RAW 264.7 cells. Western blotting analysis of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression was done in LPS- and IFN-gamma-treated mouse macrophage RAW 264.7 cells. Rats were given subcutaneous injections of AOM (15 mg/kg body wt) once a week for 3 weeks to induce ACF. They also received the experimental diet containing 0.01 or 0.05% garcinol for 5 weeks, starting 1 week before the first dosing of AOM. AOM exposure produced 97 +/- 15 ACF/rat at the end of the study (week 5). Dietary administration of garcinol caused significant reduction in the frequency of ACF: 72 +/- 15 (26% reduction, P < 0.01) at a dose of 0.01% and 58 +/- 8 (40% reduction, P < 0.001) at a dose of 0.05%. Garcinol administration significantly lowered PCNA index in ACF. Feeding of garcinol significantly elevated liver GST and QR activities. In addition, garcinol could suppress O(2)(-) and NO generation and expression of iNOS and COX-2 proteins. These findings might suggest possible chemopreventive ability of garcinol, through induction of liver GST and QR, inhibition of O(2)(-) and NO generation and/or suppression of iNOS and COX-2 expression, on colon tumorigenesis.
Carcinogenesis 2000 Jun
PMID:Prevention of colonic aberrant crypt foci by dietary feeding of garcinol in male F344 rats. 1083 8


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