Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reports of complications due to estrogen-progestagen combinations are summarized. Common minor symptoms include nausea, abdominal distress, headache, depression, and weight gain. Some of these are directly due to the pill, but others are not; for instance, depression may result from pyrodoxine deficiency, but psychodynamic factors explain the problem in others. Effects on the reproductive organs include secondary amenorrhea in about 2 of every 1000 women; structural and functional changes of the ovaries, uterus, and cervix; increase in incidence of yeast vulvovaginitis; and inhibition of lactation. Most changes in laboratory values of various constituents of blood and other body fluids reflect changes in hepatic function. Thromboembolic diseases, hypertension, and hypertriglyceridemia are rare but more serious conditions for which the pill may be responsible in some cases. Contribution of the pill to carcinogenesis and fetal abnormalities has not been proven.
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PMID:Clinical complications of oral contraceptives. 109 Jan 18

Epidemiological evidence for prenatal carcinogenesis includes associations between cancer in young people and intrauterine exposure to X-rays, drugs and hormones and prezygotic events such as specific chromosomal aberrations associated with specific cancers. Recent findings suggest that the hormonal environment during early gestation can result not only in the development of clear-cell adenocarcinoma of the vagina but also in the development of germ cell tumours of the testes and ovary. Hormone-related risk factors for testicular germ cell neoplasms include maternal use of exogenous oestrogens during early gestation and, possibly, maternal nausea, maternal obesity and race as well. Ovarian germ cell tumours also appear to be related to maternal use of hormones and obesity. Several epidemiological studies of cancer in young people have been directed towards suggested associations with parental occupational exposures, parental cigarette smoking and household exposures to electric and magnetic fields (EMF). The findings of the many studies of parental occupational exposures are inconsistent and are often nonspecific with respect to the type of childhood cancer and the job exposure implicated. Parental cigarette smoking has been associated in some studies with an increased risk for cancer among children and young adults, and in other studies with an increased risk among mature adults, but the findings are not consistent across studies. Three studies of all types of childhood cancer found risk to be related to household exposures to EMF; in all three, the risk for central nervous system tumours was increased, and in two of the three leukaemia risk as well. A fourth study showed no association between childhood leukaemia and EMF. A hypothesis is proposed which suggests that prenatal and early childhood exposure to N-nitroso compounds (NOC) may be related to the development of primary tumours of the brain in children. Experimentalists have shown that various NOC are potent nervous system carcinogens, particularly when animals are exposed transplacentally. This experimental model and findings from a Los Angeles case-control study (209 pairs) of brain tumours in young people led to the proposed epidemiological hypothesis. Although this and other epidemiological studies of NOC have major limitations, findings from epidemiological studies of congenital defects and of other childhood cancers lend the hypothesis some support. A large international collaborative case-control study of childhood brain tumours was begun recently. This study has a major advantage over most case-control studies in adults because the exposure period of greatest interest (gestation) is clearly defined.
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PMID:Epidemiological studies of perinatal carcinogenesis. 268 Sep 50

Photosensitizers were first used to treat psoriasis 15 years ago when the phototoxic reaction of psoralens and UVA was found to induce remissions of the disease. The effect of this reaction on DNA, particularly the formation of cross-links, was thought to be the decisive event. Strong cross-linking agents such as 8-MOP, TMP and 5-MOP are clinically effective whereas most compounds which produce only monofunctional adducts are virtually ineffective. Orally administered 8-methoxypsoralen (8-MOP) is the most widely used compound. 4,5',8-Trimethylpsoralen (TMP) is poorly absorbed from the intestine but has marked efficacy when applied topically. 5-MOP may be a useful alternative to 8-MOP because it is less erythemogenic and does not cause nausea. These three furocoumarins appear to be similar photochemically and may introduce similar risks. However, the photobiological properties of furocoumarins can be modified by altering one or more parts of the molecule. Such modifications might yield effective analogues with reduced cytogenetic hazards. Several psoralens and angular furocoumarins are being tested for effectiveness combined with fewest long-term side-effects, especially carcinogenesis. Encouraging preliminary results have been obtained with 7-methyl-pyridopsoralen and 4,6,4'-trimethylangelicin. Other important approaches to increasing the safety of photochemotherapy may be the use of different photoactivating wavelengths or the introduction of new classes of photosensitizers.
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PMID:Photosensitizing compounds in the treatment of psoriasis. 269 31

A questionnaire survey of British tanning salon clients disclosed that immediate side effects occurred more frequently in women using oral contraceptives. 20 questionnaires distributed to each of 146 UV-A lamp tanning salons nationwide in 1985 covered 24 questions on topics such as age, sex and skin type of the respondents, skin conditions such as acne and psoriasis, satisfaction with tan, and side effects including erythema (redness), itching, rash and nausea. Half of the subjects were young women aged 15-30, who had used the sunbed 10 to 100 times (median 20 times). Most sessions lasted 30 minutes. 98% reported that they tanned; 83% claimed they felt more relaxed; 28% complained of itching; 8% had rash or nausea. Among those with side effects, 41% with itching took oral contraceptives, compared to 27% who did not (p.005). 17% of pill users had nausea and 14% got a rash, compared to 10 and 7% of non-pill users, respectively (p.025). 195 or 19% of the 1013 respondents were on the pill. There are several conditions known to predispose to skin reddening, irritation or possibly carcinogenesis: fair skin; idiopathic light sensitivity; use of certain cosmetics or drugs such as antibiotics, antihypertension drugs, or antipsychotic agents.
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PMID:Use of UV-A sunbeds for cosmetic tanning. 373 Feb 79

Gastric hypomotility, loss of appetite, nausea, and vomiting frequently accompany critical infectious illness, radiation sickness, and carcinogenesis. The present studies examined the possibility that the pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), may be responsible for provoking some of these autonomic signs associated with illness. Gastric motility of urethane-anesthetized rats was prestimulated with intracisternal applications of thyrotropin-releasing hormone (TRH), a peptide known to activate parasympathetic vagal excitatory pathways to the stomach. Microinjection of TNF-alpha (as low as 0.02 fmol) directly into the dorsal vagal comples (DVC) suppressed TRH-stimulated gastric motility for prolonged periods of time. Duration of suppression ranged from 5 min to more than an hour, dependent on both the dose of TNF-alpha and accuracy of placement of the microinjection within the DVC. This suppression demonstrated a dose-dependent effect of TNF-alpha that required an intact vagal pathway. These studies indicate that TNF-alpha may represent a unique cytokine 'afferent' signal which directly regulates the excitability of vago-vagal reflex circuits resulting in altered gastric motility during disease states.
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PMID:Tumor necrosis factor-alpha in the dorsal vagal complex suppresses gastric motility. 852 Nov 42

A 25 year-old woman experienced a sudden onset of epigastralgia with nausea, and consulted our hospital. Because the abdominal pain did not subside with medication, she was hospitalized. On physical examination she had a slight tenderness of the right upper abdominal quadrant. Laboratory studies disclosed increases in the serum alkaline phosphatase, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and serum amylase levels. Abdominal ultrasonography, computed tomography, and endoscopic retrograde cholangiopancreatography revealed choledocholithiasis and a pancreatic duct which originated from the common bile duct. A common bile duct stone was removed with a basket catheter after an endoscopic sphincterotomy was performed. Since an anomalous union of a pancreatobiliary duct is a high risk factor of gallbladder cancer, laparoscopic cholecystectomy was perfomed. The post-operative course was uneventful and she was discharged on the twentieth post-operative day. In a microscopical examination of the resected specimen, a pyloric type gastric mucosa was clearly evident in the submucosa, while the remaining gallbladder demonstrated chronic cholecystitis. Some cases of heterotopic gastric mucosa in the gallbladder come from metaplasia, and metaplasia is also one of the most important factors in the carcinogenesis of gallbladder cancer. In conclusion, the present case is the first report of gastric mucosa with an anomalous union of the pancreatobiliary duct. Heterotopic gastric mucosa in the gallbladder may be one of the causes of gallbladder cancer, and close attention should, therefore, be paid to any occurrence of heterotopic gastric mucosa in this region.
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PMID:Heterotopic gastric mucosa in a gallbladder with an anomalous union of the pancreatobiliary duct: a case report. 984 91

Reactions to oral contraceptive therapy tend to be maximal during the first few months of use. They include nausea or epigastric discomfort, malaise, dizziness, nervousness, fatigue, weakness, leg cramps, headache, and depression. The estrogenic component is thought to be the cause. There may also be a psychogenic basis reflecting apprehension. Breast tenderness is an occasional complaint and intermenstrual spotting or breakthrough bleeding is often reported. Increasing dosage has reduced this symptom. Dysmenorrhea prior to treatment may be improved but occasionally it is aggravated. Drug-induced amenorrhea presents a double problem in that failure to resume medication 7 days after completion of a cycle results in a risk of conception. Episodes of severe uterine bleeding in patients discontinuing use after several months or years have been reported. Other side effects include a skin reaction resembling acne, pruritus, hirsutism, thinning of scalp hair, increased skin pigmentation, and weight gain or loss. Serious vascular complications and hepatic dysfunction have been shown and deviation of thyroid function may be shown by increase of serum protein-bound iodine (PBI). Clinical signs of hyperthyroidism have not been described. Oral contraception is associated with elevated plasma cortisol (hydrocortisone) levels and decreased urinary levels of 17-hydroxycorticosteroids (17-OCHS). Suppression of ovarian activity by oral contraceptives is rapidly reversible. Fear of carcinogenesis has caused much alarm but no proof as of the present time. Safety of long term use will require additional years of experience.
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PMID:Side-effects and possible complications of oral contraceptive drugs. 1225 41

Aberrations in cell cycle control occurs in the majority of human malignancies due to inactivation of tumor suppressor gene Rb by the phosphorylation induced by "hyperactive" cyclin-dependent kinases. Thus, it is quite reasonable to design cdk modulators for the prevention and treatment of human neoplasms. In order to target the cdk complexes, 2 main strategies were considered: to target the ATP binding site of cdks (direct cdk modulators) and to target upstream pathways required for cdk activation (indirect cdk modulators). Examples for the first group include flavopiridol, roscovitine, BMS-387032. Examples for the second group include perifosine, lovastatin, UCN-01. The first example of a direct small molecule cdk modulator tested in the clinic, flavopiridol, is a pan-cdk inhibitor that not only promotes cell cycle arrest but also halts transcriptional elongation, promotes apoptosis, induces differentiation and has antiangiogenic properties. Clinical trials with this agent were performed with at least 3 different schedules of administration: 1 hour infusion, 24 hour infusion and 72 hour infusion. Main toxicities for infusions >/=24 hours are secretory diarrhea and pro-inflammatory syndrome. In addition, patients receiving shorter infusions have nausea/vomiting and neutropenia. Some clinical responses were observed in several patients with refractory malignancies. Based on these encouraging results, a Phase 3 trial comparing standard combination chemotherapy versus combination chemotherapy plus flavopiridol is currently under investigation. The second example of direct small molecule cdk modulator tested in clinical trials is UCN-01 (7-hydroxi-staurosporine). UCN-01 has interesting preclinical features: inhibits ca2+-dependent PKCs, promotes apoptosis, arrest cell cycle progression at G1/S and abrogates checkpoints upon DNA damage. The first Phase I trial of UCN-01 demonstrated a very prolonged half-life. Based on this novel feature, UCN-01 is administered as a 72 hour continuous infusion every 4 weeks (second and subsequent cycles UCN-01 is administered as a 36-hour infusion). Other shorter schedules (i.e., 3 hours) are being tested. Dose-limiting toxicities include nausea/vomiting, hypoxemia and insulin-resistant hyperglycemia. Combination trials with cisplatin and other DNA-damaging agents are being tested. Recently, Phase I trials with two novel small molecule cdk modulators, BMS 387032 and R-Roscovitine (CYC202), have commenced with good tolerability. Phase 2 trials and Phase I trials in combination with standard chemotherapy is being planned with these agents. In summary, novel small molecule cdk modulators are being tested in the clinic with interesting results. Although these small molecules are directed towards a very prevalent cause of carcinogenesis, we need to test them in advanced clinical trials to determine the future of this class of agents for the prevention and therapy of human malignancies.
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PMID:Novel small molecule cyclin-dependent kinases modulators in human clinical trials. 1450 85

Aberrations in cell cycle progression occur in the majority of human malignancies. The main pathway affected is the retinoblastoma (Rb) pathway. The tumor suppressor gene Rb is an important component in the G(1)/S transition and its function is abnormal in most human neoplasms. Loss in Rb function occurs by the hyperactivation of the cyclin-dependent kinases (cdk's). Therefore, modulation of cdk's may have an important use for the therapy and prevention of human neoplasms. Efforts to obtain small-molecule cdk modulators yielded two classes of modulators: direct and indirect modulators. Direct cdk modulators are small molecules that specifically target the ATP binding site of cdk's. Examples for this group include flavopiridol, roscovitine and BMS-387032. In contrast, indirect cdk modulators affect cdk function due to modulation of upstream pathways required for cdk activation. Some examples include perifosine, lovastatin, and UCN-01. The first example of a direct small-molecule cdk modulator tested in the clinic, flavopiridol, is a pan-cdk inhibitor that not only promotes cell cycle arrest but also halts transcriptional elongation, promotes apoptosis, induces differentiation, and has antiangiogenic properties. Clinical trials with this agent were performed with at least three different schedules of administration: 1-, 24- and 72-h infusions. The main toxicities for infusions >/=24-h are secretory diarrhea and proinflammatory syndrome. In addition, patients receiving shorter infusions have nausea/vomiting and neutropenia. A phase II trial of patients with advanced non-small-cell lung carcinoma using the 72-h infusion every 2 weeks was recently completed. The median overall survival for the 20 patients who received treatment was 7.5 months, a survival similar to that obtained in a randomized trial of four chemotherapy regimens containing platinum analogues in combination with taxanes or gemcitabine, or with gefitinib, a recently approved EGFR inhibitor for the treatment of advanced lung cancer. Based on these encouraging results, a phase III trial comparing standard combination chemotherapy versus combination chemotherapy plus flavopiridol is currently under investigation. The second example of direct small-molecule cdk modulator tested in clinical trials is UCN-01 (7-hydroxystaurosporine). UCN-01 has interesting preclinical features: it inhibits Ca(2+)-dependent PKCs, promotes apoptosis, arrests cell cycle progression at G(1)/S, and abrogates checkpoints upon DNA damage. The first phase I trial of UCN-01 demonstrated a very prolonged half-life. Based on this novel feature, UCN-01 is administered as a 72-h continuous infusion every 4 weeks (in second and subsequent cycles UCN-01 is administered as a 36-h infusion). Other shorter schedules (i.e. 3 h) are being tested. Dose-limiting toxicities include nausea/vomiting, hypoxemia, and insulin-resistant hyperglycemia. Combination trials with cisplatin and other DNA-damaging agents are being tested. Recently, phase I trials with two novel small-molecule cdk modulators, BMS 387032 and R-Roscovitine (CYC202), have commenced with good tolerability. In summary, novel small-molecule cdk modulators are being tested in the clinic with interesting results. Although these small molecules are directed towards a very prevalent cause of carcinogenesis, we need to test them in advanced clinical trials to determine the future of this class of agents for the prevention and therapy of human malignancies.
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PMID:Small-molecule cyclin-dependent kinase modulators. 1452 86

Nitrotoluenes are important intermediates in the chemical industry. 2,6-Dinitrotoluene (26DNT), 2,4-dinitrotoluene (24DNT) and 2-nitrotoluene are carcinogenic in animals and possibly carcinogenic in humans. It is therefore important to develop methods to biomonitor workers exposed to such chemicals. Hemoglobin (Hb) adducts of nitroarenes are established markers of the biological effective dose. We developed a method to measure Hb adducts in biological samples. Hb adducts were measured in rats after a single exposure (0.5 mmol/kg) of 24DNT, 26DNT, 2,4-toluenediamine (24TDA) and 26TDA. Hydrolysis of Hb from rats dosed with 24DNT yields, 4-amino-2-nitrotoluene (4A2NT) (16.3 nmol/g Hb), 24TDA (4.3 nmol/g Hb) and 4-acetylamino-2-aminotoluene (4AA2AT) (0.51 nmol/g Hb). Hydrolysis of Hb from rats dosed with 26DNT yields three amines, 2-amino-6-nitrotoluene (2A6NT) (2.5 nmol/g Hb), 26TDA (1.2 nmol/g Hb) and 2-acetylamino-6-aminotoluene (2AA6AT) (0.17 nmol/g Hb). A similar Hb adduct pattern was found in Chinese workers exposed to nitrotoluenes. With respect to 24DNT, 4A2NT was the predominant adduct, and the amount was approximately 24-fold higher than 24TDA. With respect to 26DNT, 2A6NT was the predominant adduct, and the amount was approximately 20-fold higher than 26TDA. With respect to the mononitrotoluenes, the Hb adduct of 2NT was present in the highest concentrations. Each worker was examined for adverse health effects linked to exposure to DNT. The health effects were compared with the Hb adduct levels using logistic regression analysis. The odds of suffering from inertia were 3.2 times higher [95% confidence interval (CI) = 1.8-5.8] when the level of 4A2NT Hb adducts increased by one log-unit. Similar odds ratios were observed with somnolence (3.1, CI = 1.4-6.9), nausea (2.4, CI = 1.3-4.3) and dizziness (5.5, CI = 1.3-24.2). These results inferred that quantification of DNT-Hb adducts provided an effective biomarker of toxicity and could be used to estimate the risk associated with a particular exposure to DNT.
Carcinogenesis 2005 Jan
PMID:Hemoglobin adducts in workers exposed to nitrotoluenes. 1547 93


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