Consideration of the use of 17?-N,N-diethylcarbamoyl-4-methyl-4-aza-5-?-androstan-3-one (4MA), a 5?-reductase inhibitor, in prostate cancer therapy

Geldof, Albert A.; Meulenbroek, M.F.A.; Dijkstra, I.; Bohlken, S.; Rao, B. Ramanath

doi:10.1007/bf01192311

Cited by 9 publications

(3 citation statements)

References 14 publications

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“…The immunohistochemical staining of BrdUrd-incorporating cells has been described before (Geldof et al 1992). Briefly, cells were fixed in acetone ( -20 ~ and sequentially incubated in formamide/citrate to hydrolyse DNA, with monoclonal anti-BrdUrd antibody and with secondary rabbit antimouse peroxidase they were then stained with diaminobenzidine (metal-enhanced DAB, Pierce, Rockford, USA).…”

Section: Bromodeoxyuridine (Brdurd) Incorporation Assaymentioning

confidence: 99%

Nerve growth factor stimulates in vitro invasive capacity of DU145 human prostatic cancer cells

Geldof

Kleijn

Rao

et al. 1997

J Cancer Res Clin Oncol

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The prevalence of nerve growth factor (NGF) production in different human prostatic tumor cell lines (DU145, PC-3, LNCaP-FGC) was investigated using a specific enzyme-linked immunosorbent assay (ELISA) and compared to that of different human and rat prostatic tissue samples. In addition, the biological effects of NGF beta addition to the human prostatic cancer cell cultures were investigated. The ELISA technique showed the DU145 cell line to secrete measurable levels of NGF in the culture medium. When neurite-outgrowth determination in a pheochromocytoma cell line was used as a bioassay, the NGF synthesized by DU145 cells was confirmed to exhibit functional biological activity. No effect of exogenously added NGF could be established on tumor cell proliferation, on the basis of either colorimetric tetrazolium-based staining assay or bromodeoxyuridine incorporation. Also the expression of prostate specific acid phosphatase was not influenced by NGF addition. However, the in vitro invasive capacity (Matrigel) of DU145 cells was significantly increased by inclusion of 50 ng or 100 ng NGF beta/ml culture medium. In view of the clinically well-known perineural invasion of prostate cancer cells, the possible involvement of NGF as a (paracrine) factor in prostatic cancer metastatic behavior should be investigated further.

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Section: Bromodeoxyuridine (Brdurd) Incorporation Assaymentioning

confidence: 99%

Nerve growth factor stimulates in vitro invasive capacity of DU145 human prostatic cancer cells

Geldof

Kleijn

Rao

et al. 1997

J Cancer Res Clin Oncol

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“…This altered responsiveness of the HPA axis to stress in pregnancy is induced by the actions of allopregnanolone on the brain. Thus blocking allopregnanolone production in pregnant rats with overnight administration of either finasteride (a 5α-reductase inhibitor, which has been shown to reduce brain allopregnanolone content by up to 90%) (Concas et al, 1998) or 4-MA (17β-(N,N-diethyl)carbamoyl-4-methyl-4-aza-5α-androstan-3-one) (Geldof et al, 1992) substantially restores HPA axis responses to physical and emotional stressors (Brunton et al, 2009) (Ma S and Russell JA, unpubl.). Moreover, in males and non-pregnant females, peripheral allopregnanolone administration suppresses HPA axis responses to stress (Brunton et al, 2009;Patchev et al, 1996).…”

Section: Role Of Allopregnanolone In Hpa Axis Hyporesponsiveness In Pmentioning

confidence: 99%

Allopregnanolone in the brain: Protecting pregnancy and birth outcomes

Brunton

Russell

Hirst

2014

Progress in Neurobiology

112

105

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A successful pregnancy requires multiple adaptations in the mother's brain that serve to optimise foetal growth and development, protect the foetus from adverse prenatal programming and prevent premature delivery of the young. Pregnancy hormones induce, organise and maintain many of these adaptations. Steroid hormones play a critical role and of particular importance is the progesterone metabolite and neurosteroid, allopregnanolone. Allopregnanolone is produced in increasing amounts during pregnancy both in the periphery and in the maternal and foetal brain. This review critically examines a role for allopregnanolone in both the maternal and foetal brain during pregnancy and development in protecting pregnancy and birth outcomes, with particular emphasis on its role in relation to stress exposure at this time. Late pregnancy is associated with suppressed stress responses. Thus, we begin by considering what is known about the central mechanisms in the maternal brain, induced by allopregnanolone, that protect the foetus(es) from exposure to harmful levels of maternal glucocorticoids as a result of stress during pregnancy. Next we discuss the central mechanisms that prevent premature secretion of oxytocin and consider a role for allopregnanolone in minimising the risk of preterm birth. Allopregnanolone also plays a key role in the foetal brain, where it promotes development and is neuroprotective. Hence we review the evidence about disruption to neurosteroid production in pregnancy, through prenatal stress or other insults, and the immediate and long-term adverse consequences for the offspring. Finally we address whether progesterone or allopregnanolone treatment can rescue some of these deficits in the offspring.

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“…1) have also shown effectiveness in vitro and in vivo. [11][12][13][14] In previous studies, 15) we found that the C-4 chloro analog combined with a C-17 benzoyloxy group on the progesterone skeleton exhibited a higher antiandrogenic activity than the C-4 bromo compound. This phenomenon could probably be explained by taking into consideration the higher electronegativity of C-4 chlorine atom as compared to the C-4 bromo compound.…”

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confidence: 99%

New Progesterone Esters as 5.ALPHA.-Reductase Inhibitors.

Cabeza

Heuze

Bratoeff³

et al. 2001

CHEMICAL & PHARMACEUTICAL BULLETIN

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The pharmacological activity of four new progesterone derivatives: 4-bromo-17a a-(p-fluorobenzoyloxy)-4-pregnene-3,20-dione (7), 4-bromo-17a a-(p-bromobenzoyloxy)-4-pregnene-3,20-dione (8), 4-bromo-17a a-(pchlorobenzoyloxy)-pregnene-3,20-dione (9) and 4-bromo-17a a-(p-toluoyloxy)-4-pregnene-3,20-dione (10) was determined. These compounds were evaluated as 5a a-reductase inhibitors on gonadectomized hamster seminal vesicles and flank organs. The pharmacological data of this study indicate that compounds 7 and 9 having at C-17 pfluorobenzoyloxy and p-chlorobenzoyloxy ester functions respectively showed the highest antiandrogenic effect as measured by the reduction of the weight of the seminal vesicles. In the flank organ model, the same compounds 7 and 9 exhibited a smaller diameter, 1.8 and 1.0 mm, respectively, than the commercially available finasteride 3 (2.3 mm), thus indicating a higher inhibitory effect on 5a a-reductase enzyme. Steroid 7 showed a higher inhibitory activity on the conversion of T to DHT (Fig. 3) than the presently used finasteride, thus indicating a higher antiandrogenic effect. The nonsubstituted benzoyloxy ester (compound 15) showed a lower antiandrogenic activity as measured in the seminal vesicles model than the p-substituted benzoyloxy compounds.

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Consideration of the use of 17?-N,N-diethylcarbamoyl-4-methyl-4-aza-5-?-androstan-3-one (4MA), a 5?-reductase inhibitor, in prostate cancer therapy

Cited by 9 publications

References 14 publications

Nerve growth factor stimulates in vitro invasive capacity of DU145 human prostatic cancer cells

Nerve growth factor stimulates in vitro invasive capacity of DU145 human prostatic cancer cells

Allopregnanolone in the brain: Protecting pregnancy and birth outcomes

New Progesterone Esters as 5.ALPHA.-Reductase Inhibitors.

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