Effect of Treatment with Phenformin, Diphenylhydantoin or L -Dòpa on Life Span and Tumour Incidence in C3H/Sn Mice

Gerontology (Impact Factor: 3.06). 02/1980; 26(5):241-6. DOI: 10.1159/000212423
Source: PubMed


The chronic treatment of female C3H/Sn mice with phenformin (2 mg/day) and diphenylhydantoin (2 mg/day) prolonged mean life span by 23 and 25%, respectively, and decreased spontaneous tumour incidence by 4.0 and 2.3 times, respectively. The chronic treatment of mice with L-dopa (2 mg/day) did not change these parameters and decreased the multiplicity of mammary tumours. The mechanisms of the drug action on mouse life span and tumour incidence are discussed.

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    • "This caused progressive alteration of homeostasis, metabolic disturbances, leading to age-related diseases [6-13]. In other words, there is an age-related loss of sensitivity by the hypothalamus to the negative feedback of certain hormones, such as estrogens and glucocorticoids [6-13]. This explains the development of age-related diseases, including metabolic disorders and menopause. "
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    ABSTRACT: A recent ground-breaking publication described hypothalamus-driven programmatic aging. As a Russian proverb goes "everything new is well-forgotten old". In 1958, Dilman proposed that aging and its related diseases are programmed by the hypothalamus. This theory, supported by beautiful experiments, remained unnoticed just to be re-discovered recently. Yet, it does not explain all manifestations of aging. And would organism age without hypothalamus? Do sensing pathways such as MTOR (mechanistic Target of Rapamycin) and IKK-beta play a role of a "molecular hypothalamus" in every cell? Are hypothalamus-driven alterations simply a part of quasi-programmed aging manifested by hyperfunction and secondary signal-resistance? Here are some answers.
    Aging 07/2013; 5(7). · 6.43 Impact Factor
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    • "Since then, many other authors have described anti-tumour activity of biguanides in animal models and cell lines. For instance, phenformin has been shown to exert antitumour activity in different animal models (Dilman and Anisimov, 1980; Caraci et al, 2003) and to enhance the anti-tumour effects of established chemotherapy agents against squamous cell carcinoma , hepatoma-22a and lung cancer in mice (Dilman and Anisimov, 1979). Treatment of the neuroblastoma SH-SY5Y tumour cell line with increasing concentrations of phenformin reduced tumour proliferation and induced apoptosis (Caraci et al, 2003). "
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    ABSTRACT: Observations that diabetics treated with biguanide drugs have a reduced risk of developing cancer have prompted an enthusiasm for these agents as anti-cancer therapies. We sought to determine the efficacy of the biguanide phenformin in the chemoprophylaxis and in the treatment of oestrogen receptor (ER)-positive MCF7 and receptor triple-negative MDAMB231 xenografts in immunocompromised mice. We also compared the efficacy of phenformin and metformin in the treatment of MDAMB231. Immunocompromised mice were divided into groups: (1) phenformin administered for 2 weeks prior to cell injection; (2) established tumours treated with phenformin; (3) established tumours treated with metformin (only for MDAMB231 tumours); (4) untreated controls. Post-treatment tumours, liver and spleen were harvested for further analysis. Phenformin significantly inhibited both the development and growth of MCF7 and MDAMB231 tumours, and for MDAMB231 at greater efficacy than metformin without murine toxicity. The number of mitotic figures was significantly fewer in xenografts treated with phenformin compared with controls. Results suggested that the mechanism of action of phenformin in vivo is consistent with AMPK activation. Phenformin has clinical potential as an antineoplastic agent and should be considered for clinical trials both in ER-positive and triple-negative breast cancer.
    British Journal of Cancer 02/2012; 106(6):1117-22. DOI:10.1038/bjc.2012.56 · 4.84 Impact Factor
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    • "Phenformin has been shown to have anti-neoplastic activity, including p21 cell-cycle inhibition leading to apoptosis. Moreover, phenformin was shown to reduce tumor growth in several animal models [12] [13] [14] [15] [16]. While risk/benefit considerations clearly favor use of metformin over phenformin for treatment of diabetes, the risk of phenformin-associated lactic acidosis is low enough that this agent certainly would not be contraindicated for cancer treatment if it had demonstrated superior antineoplastic activity. "
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    ABSTRACT: Epidemiologic and laboratory data suggesting that metformin has antineoplastic activity have led to ongoing clinical trials. However, pharmacokinetic issues that may influence metformin activity have not been studied in detail. The organic cation transporter 1 (OCT1) is known to play an important role in cellular uptake of metformin in the liver. We show that siRNA knockdown of OCT1 reduced sensitivity of epithelial ovarian cancer cells to metformin, but interestingly not to another biguanide, phenformin, with respect to both activation of AMP kinase and inhibition of proliferation. We observed that there is heterogeneity between primary human tumors with respect to OCT1 expression. These results suggest that there may be settings where drug uptake limits direct action of metformin on neoplastic cells, raising the possibility that metformin may not be the optimal biguanide for clinical investigation.
    Biochemical and Biophysical Research Communications 11/2011; 414(4):694-9. DOI:10.1016/j.bbrc.2011.09.134 · 2.30 Impact Factor
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