Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The kinetics of accumulation of the premutagenic DNA adduct O6-methylguanine (O6-meG) in the liver, blood leukocytes, lymph nodes and bone marrow of rats was examined and compared after single or multiple doses of procarbazine, a methylating cytostatic drug employed in the treatment of Hodgkin's lymphoma patients, and methylnitrosourea (MNU), an experimental methylating agent and carcinogen. Maximal O6-meG levels occurred 1-2 h after administration of single doses of procarbazine (10 mg/kg) or MNU (1 mg/kg), thereafter decreasing with half-lives of approximately 20-45 h, depending on the tissue. A relatively uniform tissue distribution was observed with both agents, with the liver generally showing highest adduct levels, followed by the lymph nodes, bone marrow and blood leukocytes which contained broadly similar amounts of O6-meG. During daily, oral administration to rats of procarbazine for 10 days at dose rates of 2.5, 5, 10 or 20 mg/kg/day (treatment analogous to that of the MOOP chemotherapy protocol for Hodgkin's lymphoma) followed by animal death on different days (in each case 24 h after the last treatment), a biphasic mode of O6-meG induction was observed: an initially steep build-up during the first 3-4 days was followed by a transient decline in the rate of accumulation, in turn followed by a second wave of accumulation and then a further slow-down. During the same treatment, liver O6-methylguanine-DNA alkyltransferase (AGT) declined in a dose-related manner. AGT recovery after the end of treatment was slow, taking nearly 20 days after the end of the high-dose treatment to return to control levels, despite the fact that all detectable adducts had been lost from DNA within 3 days after the end of treatment. A similar depletion and slow recovery of AGT in the liver, blood lymphocytes, bone marrow and lymph nodes was observed after treatment with a single dose of 100 mg/kg procarbazine. In contrast to these observations, O6-meG accumulated smoothly during a 10 day administration of MNU (1 or 10 mg/kg/day) to reach a steady-state within 5-6 days, while liver AGT was partially depleted after the high dose and recovered fully within 72 h of cessation of treatment. Similarly, a single dose of MNU (35 mg/kg) resulted in AGT depletion followed by rapid recovery in all four tissues examined. It is concluded that procarbazine (but not MNU) causes a decrease in cellular AGT concentrations by a mechanism additional to suicide repair of O6-meG.(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinogenesis 1994 Aug
PMID:Differential effects of procarbazine and methylnitrosourea on the accumulation of O6-methylguanine and the depletion and recovery of O6-alkylguanine-DNA alkyltransferase in rat tissues. 751 72

Alternative splicing of ten different variant exons (v1-v10) is responsible for the creation of a large number of different CD44 surface proteins. Some of these proteins play decisive roles in the metastatic spread of rat tumours. Also in human cancers, CD44 splice variants are frequently expressed in advanced states of tumorigenesis. In breast cancer and in non-Hodgkin's lymphomas expression of exon v6 is correlated with poor prognosis of patient survival. In colorectal carcinogenesis, expression of exon v5 is an early tumour marker since it is already detectable on small dysplastic polyps (but not on normal colon epithelium). In contrast, exon v6 expression occurred with increased frequency with tumour progression, and its expression on colorectal tumours indicated reduced survival probability. Most likely, tumours carrying the CD44 v6 epitope acquire selective advantage during tumour progression and metastasis formation. This could be a proliferative advantage since mice transgenic for the CD44 isoform CD44v4-v7 on T lymphocytes show an accelerated T-dependent immune response as compared with non-transgenic siblings.
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PMID:CD44 in colon cancer. 757 2

The authors report 4 patients, without a history of tobacco or alcohol abuse, who developed squamous cell carcinoma of the esophagus secondary to mediastinal irradiation. Carcinoma of the esophagus developed in 3 women 8-11 years after mediastinal radiotherapy for breast cancer and in a man 9 years after mediastinal radiotherapy for Hodgkin's disease. Three patients underwent resection, with intrathoracic anastomosis in 2 and cervical in 1. No fistulae were observed despite the presence of esophageal fibrosis. No mediastinal lymph node was metastatic. Patients survived 7, 16, and 26 months, respectively, after resection. This study confirms the concept of radiation-induced carcinogenesis. We conclude that patients with dysphagia and a history of previous mediastinal radiotherapy should undergo repeated endoscopy for biopsy.
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PMID:Esophageal cancer after mediastinal irradiation. 801 Oct 16

The authors report 4 patients, without a history of tobacco or alcohol abuse, who developed squamous cell carcinoma of the esophagus secondary to mediastinal irradiation. Carcinoma of the esophagus developed in 3 women 8-11 years after mediastinal radiotherapy for breast cancer and in a man 9 years after mediastinal radiotherapy for Hodgkin's disease. Three patients underwent resection, with intrathoracic anastomosis in 2 and cervical in 1. No fistulae were observed despite the presence of esophageal fibrosis. No mediastinal lymph node was metastatic. Patients survived 7, 16, and 26 months, respectively, after resection. This study confirms the concept of radiation-induced carcinogenesis. We conclude that patients with dysphagia and a history of previous mediastinal radiotherapy should undergo repeated endoscopy for biopsy.
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PMID:Esophageal cancer after mediastinal irradiation. 800 9

The accumulation of O6-methylguanine (O6-meG) in the DNA of blood leukocytes of 21 Hodgkin's lymphoma patients (followed for up to 12 cycles of treatment) treated in the context of MOPP combination chemotherapy with 150 mg procarbazine daily for 10 days was examined and compared to that observed in rats treated with different doses of procarbazine as a single agent once per day for 10 days. In humans, the adduct accumulated in a dose-related fashion and appeared to approach a steady-state after 7-8 days of treatment. Adduct levels on day 10 of the treatment cycle averaged 0.25 +/- 0.09 (mean +/- SD) mumol/molG and, for different individuals, covered a 3-fold range. Intra-individual variability between different treatment cycles was much more limited than inter-individual variability, the two parameters accounting for 8.9% and 84.5% respectively of adduct variance at a constant cumulative dose. Comparison of the dose-response relationships for humans and rats indicates that, under conditions of no depletion of O6-alkylguanine-DNA alkyltransferase (AGT), O6-meG accumulates in blood leukocyte DNA of humans at a rate which is only approximately 2-fold lower than in rats, implying that, to the extent to which O6-meG contributes to the genotoxic activity of procarbazine, human susceptibility to it is likely to be comparable to that of the rat. This is likely to be true also of the bone marrow (the tissue of interest as a target tissue for leukaemogenesis), since the tissue distribution of O6-meG induced by low doses of procarbazine in rats, mice and rabbits indicated that blood leukocyte levels of this adduct closely reflect those in the bone marrow. Based on these results, it is estimated that by the end of a MOPP chemotherapy cycle O6-meG reaches levels of the order of 0.2-0.3 fmol/microgram DNA (0.3-0.5 mumol/molG) in human bone marrow (the target tissue of leukaemogenesis observed after such treatment).
Carcinogenesis 1994 Aug
PMID:Comparative dosimetry of O6-methylguanine in humans and rodents treated with procarbazine. 805 50

The mutagenic, carcinogenic and cytotoxic activity of dacarbazine, a drug employed in cancer chemotherapy, may be related to the induction in DNA of O6-methylguanine (O6-meG), a quantitatively minor but biologically important lesion. In the present study the kinetics of O6-meG formation and repair in blood leukocyte DNA were examined in 20 Hodgkins lymphoma patients treated i.v. with 180 +/- 13 (mean +/- SD) mg/m2 dacarbazine and compared with those observed in various tissues of rodents treated with different doses of the drug. In Hodgkin's lymphoma patients adduct levels reached a value of 0.27 +/- 0.14 fmol/microgram DNA 2 h after dacarbazine administration, while the rate of subsequent loss suggested an adduct half-life of < or = 30 h. Measurement of adduct levels in the same individuals after successive courses of treatment spaced 3 weeks apart (up to 10 treatment courses) demonstrated a consistent individual response and statistical analysis of variance confirmed that intra-individual variation in adduct accumulation after a given dose of dacarbazine accounted for only 5% of the total variance observed. In contrast, inter-individual variation accounted for 70% of the observed variance, with adduct levels 2 h after drug treatment varying approximately 7.5-fold among adduct-positive individuals. No significant depletion of lymphocyte O6-alkylguanine-DNA alkyltransferase (AGT) occurred after patient treatment with dacarbazine. No significant relationship between adduct levels and clinical response to treatment was observed. In rats treated with single or multiple doses of dacarbazine causing varying degrees of AGT depletion the highest levels of O6-meG were seen in the liver, followed by the lymph nodes, bone marrow and blood leukocytes, which showed up to approximately 2-fold lower levels. A similar tissue distribution was also observed in mice and in a single rabbit. These observations suggest that O6-meG levels assayed in blood leukocytes of therapeutically treated humans reflect those present in the -lymph nodes (target tissue for chemotherapy) and the bone marrow (target tissue for leukaemogenesis) and may be utilized as a measure of the drug dose reaching these tissues. The quantitative data reported in this study show that under conditions of no depletion of AGT O6-meG accumulates in blood leukocyte DNA of humans at a rate similar to that observed in rats, suggesting that human susceptibility to any O6-meG-mediated genotoxic effects of dacarbazine may be comparable with that of the rat.
Carcinogenesis 1996 Apr
PMID:Comparative study of the formation and repair of O6-methylguanine in humans and rodents treated with dacarbazine. 862 83

Organ-specific cancer incidence rates can vary dramatically between low- and high-incidence areas. Such differences are due to (1) heritable susceptibility determinants, (2) risk factors associated with the environmental and local living conditions (e.g., viruses, pollution), and (3) personal life-style factors. For organs showing large differences between cancer registries, exogenous factors might be most important, while for organs showing only small differences, endogenous and unavoidable factors are expected to be more important. In this paper, a working hypothesis based on descriptive cancer epidemiology is presented to estimate, in a quantitative manner, the unavoidable contribution to the process of carcinogenesis and to discuss limitations to individual cancer prevention. Cumulative cancer incidence rates for a 75-year period of life (CR74, in percent) were taken from IARC Scientific Publication No. 120 (1992). For each organ, values were ranked in ascending order, and the ratio between high-rate and low-rate registries (90th percentile/10th percentile) was determined. This measure of variability among registries differed strongly between organs. Largest ratios were seen for organs with well-known exogenous risk factors, such as pharynx, lip, tongue, mouth, liver, esophagus, and melanoma in males, and lung, esophagus, gallbladder, liver, and bladder in females. Small ratios were seen for rectum, brain, colon, and Hodgkin's disease in males, and breast, rectum, ovary, brain, and colon in females. It is concluded that the process of carcinogenesis in the latter organs has a stronger endogenous/unavoidable component, for some tissues possibly of hormonal type. A fictitious population was composed where, for each organ, the minimum reported cancer rate was taken. When based on all cancer registries world-wide, CR74 sums over all sites of 2.0% and 2.3% resulted in males and females, respectively. When only Central/Western European countries were included in the analysis in order to reduce differences in risk factors nos. 1 and 2, the sum of the minimum values was 10.4% and 8.7%. After correction of the data for smoking, 'minimum' cancer incidence rates in males and females were estimated to be 7.6% and 6.8%. Based on a median cancer incidence rate for nonsmoking males in Europe of about 21%, therefore, individual preventive measures taken by a nonsmoker can reduce the cancer risk, on average, 'only' by a factor of about 3. A considerable fraction of cases thus appears to be hardly avoidable.
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PMID:Endogenous and exogenous factors in carcinogenesis: limits to cancer prevention. 872 Feb 82

One in 600 children 0-16 years of age develop cancer, and 60% to 70% of them are cured. Projection of the data indicates that by the turn of the century, 1 of every 900 individuals between the ages of 16 and 44 years will be a cancer survivor. In the adult population, carcinogens and irradiation play a major role in oncogenesis. In the pediatric population other factors are probably dominant. Children of low socioeconomic groups, with nutritional deficiencies, are more exposed to viral infections at a very early age and have a greater chance of developing tumors such as Burkitt lymphoma or mixed cellularity Hodgkin disease. Other factors such as hormone-assisted conception or in vitro fertilization may have carcinogenic potential, although this has yet to be determined. Maternal diet during pregnancy, especially low folic acid consumption periconception, may have bearing on the fetus's risk of developing malignancy. The hazards of exposure to electric and magnetic fields from high-voltage transmission lines, home electric appliances, video display terminals, or residence near nuclear plants, although very doubtful, are included in the list of cancer promoters in children. Activated oncogenes, mutated suppressor genes, mismatch repair genes, nucleotide excision genes, and loss of imprinting genes are beginning to evolve as important factors in carcinogenesis. The more in-depth information on genetic and environmental factors should provide new data on the evolution of pediatric tumors and possibly on their prevention.
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PMID:Pediatric cancer: environmental and genetic aspects. 883 38

Ionizing radiation is a well-known risk factor of cancer development, but the mechanism of radiation induced carcinogenesis is not clear. Chromosomal rearrangements induced by radiation most likely are one of the principal genetic alterations resulting in malignant transformation. The chimeric BCR-ABL associated with chronic myelogenous leukemia (CML) and H4-RET oncogenes associated with thyroid papillary carcinoma are the result of a translocation and inversion, respectively. In vitro studies showed these genes were induced by high-doses of X-irradiation in cell lines. Studies also show that therapeutic external X-ray doses as high as 60 Gy for treatment of various childhood cancers including Hodgkin's disease significantly increase the risk of thyroid cancer. Therefore, we examined the induction and persistence of these chimeric genes in human thyroid tissues transplanted in scid mice after 50 Gy exposure as a function of time for 2 months to elucidate the early events of thyroid carcinogenesis. The H4-RET genes were detected on day 2 and throughout the 2 month period. On the other hand, BCR-ABL genes were detected on day 2 and were undetectable subsequently. These results suggest that ionizing radiation causes various oncogene activations, but cells with only specific gene alteration uniquely associated with thyroid carcinogenesis are selectively retained demonstrating one of the early events in the beginnings of radiation carcinogenesis in human thyroid tissues.
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PMID:Continued expression of a tissue specific activated oncogene in the early steps of radiation-induced human thyroid carcinogenesis. 933 21

Tumorigenesis has been shown to proceed through a series of genetic alterations involving protooncogenes and tumor suppressor genes. However, the investigation of genomic instability of microsatellites has disclosed a new mechanism for human carcinogenesis, which is involved not only in hereditary nonpolyposis colon cancer (HNPCC) but in a number of other malignancies as well. To determine whether microsatellite instability is involved in Hodgkin's disease, we screened 16 such tumors using 7 microsatellite marker loci on 6 chromosome arms 4, 5, 9p, 9q, 11, 14, and 17. Using the polymerase chain reaction method, DNA samples from the tumors and from normal peripheral blood leukocytes from each patient were compared for the allelic pattern produced at each locus. Five cases of genomic instability were identified, suggesting that this mechanism is relevant to the pathogenesis of HD.
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PMID:Instability of dinucleotide repeats in Hodgkin's disease. 946 48


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