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

We studied the effects of hormonal manipulation by orchiectomy, alone or in combination with the aromatase inhibitor aminoglutethimide (AGT), and by luteinizing hormone-releasing hormone agonist (LH-RH-A) (goserelin) treatment on the development of early putative (pre)neoplastic lesions induced in the pancreas of rats and hamsters by azaserine and N-nitrosobis(2-oxopropyl)amine respectively. Treatment of the animals started 1 week after the last injection with carcinogen and continued for 4 months. Orchiectomy caused a significant inhibition of growth of acidophilic atypical acinar cell nodules in the rat model, whereas surgical castration did not show an effect in the hamster model. In rats, but not in hamsters, orchiectomy resulted in a significant decrease in body weight and in absolute, but not relative pancreatic weight. Treatment of the animals with AGT or goserelin did not cause a significant effect on the development of either putative preneoplastic acinar lesions in rat pancreas or early ductular lesions in hamster pancreas. Hamsters showed clearly higher plasma epidermal growth factor (EGF) and insulin-like growth factor 1 (IGF-1) concentrations than rats, while plasma testosterone levels were significantly lower. Plasma EGF and IGF-1 levels decreased with increasing age in both control and treatment groups. Compared to controls there were no clear unequivocal effects of treatment on EGF, IGF-1 and gastrin levels. Plasma testosterone levels decreased by orchiectomy and LH-RH-A treatment. In rats hormone-induced effects on food intake and altered nutritional status might be important with respect to the development of carcinogen-induced preneoplastic pancreatic lesions.
Carcinogenesis 1991 Sep
PMID:Effects of castration, alone and in combination with aminoglutethimide, on growth of (pre)neoplastic lesions in exocrine pancreas of rats and hamsters. 183 92

The formation of estrogens in mammals via aromatase involves the relatively unique capacity to form an aromatic ring de novo in contrast to most other aromatic substances (essential amino acids) which are obtained only in the diet. The reaction is the only example of a cytochrome P450 system which resides in both the mitochondrial and microsomal fractions of the cell. It occurs widely throughout the body in diverse tissues and functions via both de novo synthesis and transformation of prehormones (androstenedione and testosterone). It is found widely in animal species in both the brain and gonads even in phylogenetically primitive species. Placental aromatase appears to be associated with the evolution of viviparity and an extended gestational period in utero. Follicular aromatase which is dependent upon follicle-stimulating hormone stimulation appears to be essential for oogenesis, ovulation, and normal luteal functions while central nervous system aromatase serves to determine sexual behavior and the neurohormonal link to the hypothalamus and pituitary for ovarian cyclicity. While estrogens are the key to pituitary, breast, and endometrial growth and development, this hormone is one of the few examples of an endogenous steroid that has been implicated as a carcinogen or a stimulant for carcinogenesis.
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PMID:Biochemistry of aromatase: significance to female reproductive physiology. 708 98

One-third of human breast cancers exhibit estrogen-dependent proliferation. It appears that estrogen functions as a mitogenic factor in these carcinomas. As aromatase is the rate-limiting enzyme in estrogen biosynthesis. It could play an important role in the pathogenesis of estrogen-dependent breast cancer. The aromatase gene consists of at least six exons 1, each containing a promoter, and the tissue-specific expression is regulated by alternative use of these multiple promoters. The expression of aromatase in the breast and abdominal adipose tissues is regulated by a promoter flanking exon 1b. Molecular and epidemiological analyses of tissue-specific utilization of multiple exons 1 and promoters revealed a switching from use of the adipose-specific exon 1b to exon 1c in adipose tissues adjacent to the carcinomas in most breast cancer patients. Exon 1c has been shown to be specific for the ovary. Aromatase mRNA in adipose tissues distal to the tumour of the same patients was normally transcribed from exon 1b as was breast tissue in healthy controls. It is noteworthy that a switching from exon 1b to exon 1c was often observed in breast cancer patients having metastatic lymph nodes. These data suggest that switching from an adipose-specific exon 1b to exon 1c could cause a deviation from strict regulation of tissue-specific expression of the adipose aromatase leading to over-expression of the adipose aromatase. Consequently overproduction of local estrogen may promote carcinogenesis or proliferation of breast cancer cells.
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PMID:Molecular and epidemiological analyses of abnormal expression of aromatase in breast cancer. 758 91

The present 12-month study was carried out to investigate the effects of the aromatase inhibitor aminoglutethimide, alone and in combination with orchiectomy, on pancreatic carcinogenesis in azaserine-treated rats and N-nitrosobis(2-oxopropyl)-amine-treated hamsters. Treatment of the animals started 4 months after the last injection with the carcinogen. They were surgically castrated and/or treated with aminoglutethimide. Aminoglutethimide-treated rats developed less pancreatic tumours than did untreated controls. Multiplicity of (pre-)-neoplastic acinar lesions was lower in orchiectomized rats than in intact rats. Inhibition of pancreatic carcinogenesis was most pronounced in rats that were both orchiectomized and treated with aminoglutethimide. These effects were statistically significant after 8 months, but not after 4 months, of treatment. In hamsters, aminoglutethimide showed an enhancing rather than an inhibitory effect on the formation of ductular pancreatic tumours. Castration appeared to have no effect on the development of N-nitrosobis(2-oxopropyl)amine-induced ductular lesions in the pancreas, either alone, or in combination with aminoglutethimide. The present findings indicate that aminoglutethimide, alone and in combination with surgical castration, might be of value for the treatment of pancreatic acinar tumours, whereas the usefulness of aminoglutethimide for treatment of ductular adenocarcinomas of the pancreas is somewhat doubtful.
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PMID:Effects of aminoglutethimide, alone and in combination with surgical castration, on pancreatic carcinogenesis in rats and hamsters. 759 Dec 93

The chemopreventive activity of the aromatase inhibitors vorozole and 4-hydroxyandrostenedione were determined in the methylnitrosourea (MNU)-induced model of rat mammary tumorigenesis. Vorozole (5 and 2.5 mg/kg body wt) and 4-hydroxyandrostenedione (15 and 6 mg/rat) were administered daily (by gavage) to virgin female Sprague-Dawley rats starting at an age of 43 days. Seven days later animals were given a single dose of MNU. Following treatment with MNU, animals continued to be treated with vorozole and 4-hydroxyandrostenedione daily until the end of the experiment (100 days post MNU treatment). Vorozole at either dose proved to be a profound inhibitor of MNU-induced mammary tumors. Vorozole decreased tumor incidence from 100% to 10%, while simultaneously decreasing tumor multiplicity from 5 tumors per animal to 0.1 tumors per animal. This chemopreventive effect was accompanied by significant increases in body weight gain in the animals treated with vorozole when compared with control rats. In contrast, neither dose of 4-hydroxyandrostenedione had any effect on tumor incidence and only the higher dose slightly decreased tumor multiplicity.
Carcinogenesis 1994 Dec
PMID:Chemopreventive effects of the aromatase inhibitors vorozole (R-83842) and 4-hydroxyandrostenedione in the methylnitrosourea (MNU)-induced mammary tumor model in Sprague-Dawley rats. 800 Dec 34

The effects of structurally different antiestrogens, progesterone and the aromatase inhibitor aminoglutethimide, were evaluated for chemopreventive activity in the N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis model. Treatment with either RU 16117, progesterone or aminoglutethimide resulted in a significant decrease in cancer multiplicity [> or = 50%; P < .05] when administered individually at doses 80% of the maximally tolerated dose [MID]. Toremifene was also remarkably effective in inhibiting MNU-induced mammary tumorigenesis although this inhibition was achieved at a dose which caused a significant decrease in body weight gain. Aminoglutethimide, RU 16117 and toremifene citrate, in addition to their effects on tumor multiplicity, caused significant increases in the latency period for tumor development. Combinations of aminoglutethimide, progesterone and/or a suboptimal dose of tamoxifen citrate also proved to be effective in inhibiting the development of MNU-induced mammary cancers; however, the combination regimen was no more effective than either aminoglutethimide or progesterone administered alone. These results suggested that agents altering the hormonal environment, regardless of their mechanism of action, may provide protection against the development of hormone responsive mammary cancer.
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PMID:Chemoprevention of MNU-induced mammary tumorigenesis by hormone response modifiers: toremifene, RU 16117, tamoxifen, aminoglutethimide and progesterone. 807 89

The expression of aromatase (estrogen synthetase) is tissue specifically regulated through the alternative use of multiple exons 1 and promotors. We have determined the amounts of aromatase messenger ribonucleic acid (mRNA) and which type of multiple exons 1 of the human aromatase gene is used in breast tissues of 49 patients with breast cancer by reverse transcription-PCR analysis. The aromatase mRNA levels in these breast cancer tissues (4.53 +/- 0.66 x 10(-3) attomoles/micrograms RNA) were significantly (P < 0.01) higher than those in 16 nonmalignant breast tissues (1.73 +/- 0.40 x 10(-3) amol/micrograms RNA). Aromatase mRNA in all nonmalignant breast tissue were transcribed from skin fibroblast/fetal liver-specific exon 1 (exon 1b) of the gene. In 23 breast cancer tissues, the utilization of multiple exons 1 in the aromatase mRNA was the same as that in nonmalignant breast tissues, whereas in the other 26 cases, it changed from exon 1b to ovary-specific exon 1 (exon 1c). Such switching of tissue-specific exons 1 may affect strict regulation of the tissue-specific expression of aromatase, leading to abnormal expression of the aromatase. The consequent overproduction of local estrogen might promote carcinogenesis or the proliferation of breast cancers.
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PMID:Presence of alternatively spliced transcripts of aromatase gene in human breast cancer. 896 75

The chemopreventive activity of the highly specific nonsteroidal aromatase inhibitor, vorozole, was examined in the methylnitrosourea (MNU)-induced rat model of mammary carcinogenesis. Various doses of vorozole (0.08-1.25 mg/kg body wt/day) were administered daily (by gavage) to female Sprague-Dawley rats starting at 43 days of age. Seven days later, the rats were given a single i.v. dose of MNU (50 mg/kg body wt). Rats were continually treated with vorozole until the end of the experiment (120 days post-MNU). Vorozole caused a dose dependent inhibition of mammary cancer multiplicity. The highest dose of vorozole (1.25 mg/kg body wt/day) decreased cancer multiplicity by approximately 90%, and simultaneously decreased cancer incidence from 100 to 44%. The next two highest doses of vorozole (0.63 and 0.31 mg/kg body wt/day) inhibited MNU-induced mammary cancer multiplicity by 70-80%. Even the two lowest doses of vorozole (0.16 and 0.08 mg/kg body wt/ day) decreased cancer multiplicity -50%. Serum level determinations were performed on a variety of endpoints at either 4 or 24 h following the last dose of vorozole. Insulin-like growth factor (IGF)-1 levels were slightly, but significantly, increased by vorozole treatment. Vorozole induced striking increases in serum testosterone levels at 4 h at all the dose levels employed. Testosterone levels were significantly elevated over controls at 24 h in rats given the lower doses of vorozole (0.08-0.31 mg/kg body wt/day), but were significantly lower than in rats administered the higher doses of vorozole (0.63 or 1.25 mg/kg body wt/ day). This result presumably reflects the limited half-life of vorozole in rats. In a second series of experiments, the effects of limited duration of dosing with vorozole (2.5 mg/kg body wt/day) or intermittent dosing with vorozole were determined. Treatment of rats with vorozole for limited time periods, from 3 days post-MNU administration until 30 or 60 days post-MNU treatment, resulted in significant delays in the time to appearance of palpable cancers. However, these limited treatments did not greatly affect the overall incidence or multiplicity of mammary cancers when compared with the MNU controls at the end of the study (150 days post-MNU). Finally, the effects of intermittent dosing with vorozole (2.5 mg/kg body wt/day) were examined. Rats were administered cycles of vorozole daily for a period of 3 weeks followed by treatment with the vorozole vehicle for the next 3 weeks (total of four cycles). Although this intermittent treatment did inhibit the appearance of new tumors during each of the periods that vorozole was administered, it did not cause regression of palpable cancers.
Carcinogenesis 1998 Aug
PMID:Chemopreventive effects of the aromatase inhibitor vorozole (R 83842) in the methylnitrosourea-induced mammary cancer model. 974 27

The typical high fat, low fibre diet of the industrialised West, particularly when associated with inadequate exercise, is likely to advance the onset of puberty. This will manifest in girls as an earlier menarche, earlier onset of breast development, and an earlier growth spurt. Both earlier menarche and adult tallness are markers of increased risk to breast cancer. Earlier menarche in the West is usually associated with earlier onset of hyperinsulinaemia, and multiple case-control studies report that hyperinsulinaemia too is a marker of increased breast cancer risk. Although the Western diet is linked both to earlier menarche and also to earlier hyperinsulinaemia, the mechanism involved is not necessarily the same. While menarche is likely to be triggered by a threshold level of fatness, manifestation of insulin resistance is genetically-determined and strongly influenced by the fatty acid profile of the diet. The putative mechanisms by which they influence mammary carcinogenesis also differ. Early menarche is reported to be associated with a raised oestradiol level persisting into early adult life. On the other hand, hyperinsulinaemia is commonly associated with abnormal aromatase activity in the ovaries. In addition, the concomitant increase in bioactive levels of insulin-like growth factor-I may synergise with oestrogen in stimulating proliferative activity in mammary epithelium. Dietary modification and exercise regimens are proposed in families at high risk to breast cancer. The measures have been shown to reduce insulin levels in both children and adults, and serial monitoring of insulin and sex steroid levels could be used to detect a metabolic-endocrine effect.
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PMID:Western diet, early puberty, and breast cancer risk. 977 2

Oral anti-cancer drugs play an important role in the treatment of breast cancer. Because these hormonal agents are related to mammary carcinogenesis and tumor growth, they are used not only for therapy but also to prevent the onset of the disease. Tamoxifen, toremifene, fadrozole and other aromatase inhibitors, goserelin, leuprolin and MPA are used widely in Japan as hormonal anti-cancer drugs. In addition oral anti-cancer chemotherapeutic agents, such as cyclophosphamide, 5-FU, 5'-DFUR, FT and UFT are used for breast cancer. The combination of these hormonal and chemotherapeutic agents produces good clinical results in curing the disease. Oral drugs are superior to injected drugs with regard to the QOL of patients.
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PMID:[Recent development of oral anti-cancer drugs for breast cancer]. 1006 92


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