Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transplantable prostate adenocarcinoma were treated with polyamine biosynthetic inhibitors. alpha-difluoromethylornithine (alpha-DFMO), an inhibitor of ornithine decarboxylase and by s-methylglyoxal-bisguanylhydrazone (MGBG), an inhibitor of s-adenosylmethionine decarboxylase. The therapeutic regimen of 0.8-1.11 g/kg DFMO reduced the tumor growth by 40% whilst the combination with 10.5 mg/kg MGBG completely destroyed the prostate adenocarcinomas in the tumor-bearing animals. The polyamine content of spermidine and spermine in the cancerous tissues is significantly lower whereas the putrescine levels remain unchanged. The MGBG therapy distinctly stimulates the activity of ornithine decarboxylase and increases the putrescine concentration up to toxic levels. The application of alpha-DFMO prevented the toxic accumulation of putrescine and allowed higher doses of MGBG. Clinical trials with polyamine antimetabolites appeared useful due to pathological polyamine excretion of patients with metastatic prostate cancer. The therapy with 0.2-0.3 g/kg DFMO in patients with hormone-resistent prostate cancer and metastasis displayed a moderate anti-tumor activity following 2 months additional treatment. High levels of side effects, however, were registered and were similar to those of other cytotoxic compounds. A combined therapy with DFMO/MGBG in a patient with metastatic anaplastic prostate cancer did not improve the survival rate but showed regressive effects of the histological pattern.
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PMID:[Therapy with inhibitors of polyamine biosynthesis in refractory prostatic carcinoma. An experimental and clinical study]. 241 11

Mitoguazone (methylglyoxal-bis(guanyl-hydrazone), MGBG) was studied by its first-pass mechanism in both cancer patients and experimental cancer models. It appears from the study that 90% of MGBG is cleared from the plasma within minutes. 24-h recovery in the urine, however, did not exceed 16% so that 84% of the drug seems to be bound to subcellular compartments. Tissue levels of MGBG in the normal prostate ranged higher than in experimental prostate cancer type 3327 M/G, i.e. enhanced clearance from cancer tissues: polyamine biosynthetic enzymes ornithine decarboxylase as well as S-adenosylmethionine decarboxylase are contrarily affected by MGBG.
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PMID:Some aspects of clearance of mitoguazone in cancer patients and experimental cancer models. 351 31

Inhibitors of polyamine synthesis were tested for therapeutic effectiveness on transplantable prostate cancer. Inhibition of either ornithine decarboxylase or S-adenosyl-L-methionine decarboxylase (AMDC) by alpha-difluormethylornithine (DFMO) or methylglyoxal-bis[guanylhydrazone] (MGBG), respectively, was associated with significant antitumor effect. The combination of DFMO with MGBG was not only more effective but no more toxic than MGBG alone. Combination of MGBG with 9-B-D-arabinofuranosyladenine, an indirect effector of SAMDC, failed to increase therapeutic effectiveness of MGBG.
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PMID:Antigrowth effect of some inhibitors of polyamine synthesis on transplantable prostate cancer. 640 60

Difluoromethylornithine (DFMO) and methylglyoxal-bis(guanyl-hydrazone) (MGBG), inhibitors of ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AMDC), respectively, were tested in two experimental prostatic cancer models. DFMO resulted in a reduction in tumor size in both the rapidly growing R-3327 rat prostatic adenocarcinoma (30.5 +/- 15 versus 61 +/- 9.5 in control animals) and the human DU-145 adenocarcinomas (1.7 ml versus 3.3 ml in control animals) in nude mice. MGBG was tested only in the rat tumor, where it induced a reduction of 22.9 +/- 9.5 ml versus 61 +/- 9.5 in control animals in tumor size but was highly toxic. Flutamide or 9-B-D-arabinofuranosyladenine (Ara-A) proved ineffective per se in reducing tumor growth of the human DU-145 or of the R-3327-G strain, respectively, but increased the efficacy of DFMO against the DU-145 tumor had a high level of ODC which was reduced by DFMO of by Ara-A; the R-3327 tumor had a low level of ODC which was too low to be decreased by DFMO.
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PMID:Some effects of inhibitors of polyamine synthesis on experimental prostatic cancer. 642 51

CGP 48664A (2-(4-aminoiminomethyl)-2,3-dihydro-1H-inden-1-ylidene dihydrochloride, CAS 149400-88-4) is a new potent inhibitor of S-adenosylmethionine decarboxylase with antitumor properties. In view of the eminent clinical problems in the treatment of non hormone dependent prostatic cancer, the antiproliferative potency of this compound was tested in Dunning MAT-LyLu rat prostatic adenocarcinoma. The compound proved inefficient in preventing the growth of this tumor, even at a near toxic dose. A reason for the lacking effect is presumably the inadequate accumulation of the drug in the tumor cells due to the excessive growth rate of the MAT-LyLu xenografts. Tumor growth seems not to be accompanied by a proportionally rapid vascularization of the tumor mass. CGP 48664A was found to be a potent inhibitor of polyamine oxidase. This property of the drug may have contributed to the activation of the phagocytic capacity of peritoneal macrophages from tumor-bearing rats.
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PMID:Observations with an S-adenosylmethionine decarboxylase inhibitor in rats with prostatic adenocarcinoma. 890 Nov 56

The high levels of polyamines maintained in the prostate suggest that these compounds are important to prostate cell function and that disruption of polyamine metabolism may be an effective way to stop the growth of prostate cancer cells. The unsymmetrically alkylated polyamine analogues N1-ethyl-N11-((cyclopropyl)methyl)-4,8-diazaunde-cane (CPENSpm) and N1-ethyl-N11-((cycloheptyl)methyl)-4,8-diazaundecane (CHENSpm) have been shown previously to have cytotoxic effects in breast and non-small cell lung cancer cells. We have now investigated the responses of three human prostate cancer cell lines, LNCaP, PC3, and Du145, to these polyamine analogues and to the symmetrically alkylated analogue N1,N11-bis(ethyl)norspermine (BE 3-3-3). The Du145 cell line, in which IC50 values ranged from 0.65 to 0.8 microM, was the most sensitive to each of the polyamine analogues, although significant growth inhibition resulted in the other cell lines as well. CPENSpm and BE 3-3-3 but not CHENSpm caused significant decreases in the intracellular spermine and spermidine pools, although all three analogues accumulated to high levels in each of the cell lines. Spermidine/spermine N1-acetyltransferase activity was induced 23-250-fold in response to CPENSpm and BE 3-3-3, but it was not affected by CHENSpm. None of the analogues had significant effects on the activities of ornithine decarboxylase or S-adenosylmethionine decarboxylase. Quantitation of DNA fragmentation indicative of programmed cell death (PCD) showed that both CPENSpm and CHENSpm were effective inducers of PCD in all three prostate cell lines. In contrast, BE 3-3-3 led to PCD only in LNCaP cells. The ability to induce PCD was the only parameter measured that correlated with cell line sensitivity to these polyamine analogues.
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PMID:Effects of the polyamine analogues N1-ethyl-N11-((cyclopropyl)methyl)-4,8-diazaundecane and N1-ethylN-11-((cycloheptyl)methyl)-4,8-diazaundecane in human prostate cancer cells. 1065 27

Statistical data from prostate cancer (PCa) clinics indicates that a large patient population discovered by annual prostate specific antigen (PSA) screening may have a latent form of the disease. However, current medical tests cannot differentiate slow from fast growing PCa, resulting in many unnecessary radical treatments and morbidities. It is thus necessary to find new screening tests that enable us to differentiate between fast- and slow-growing tumors. Inspired by the reported functions of spermine in carcinogenesis, we analyzed spermine and mRNA expression levels of rate-limiting enzymes in the spermine metabolic pathway for nine cases of PCa with accurately defined PSA velocity (Vpsa). Using MR spectroscopy, histopathology, laser-capture microdissection and real-time PCR techniques, we analyzed relationships between changes in spermine levels, mRNA expression levels of spermine anabolic and catabolic enzymes and human prostate cancer growth rates represented by serum Vpsa. The expression levels of spermine anabolic enzymes: ornithine decarboxylase (ODC1) and S-adenosylmethionine decarboxylase (AMD1) in benign epithelia surrounding cancer glands was logarithmically reduced with the increase of Vpsa (ODC1, p < 0.016; AMD1, p < 0.048), and antizyme (OAZ1) expression in cancer cells was increased with the increase of Vpsa (p < 0.001). Finally, we observed an inverse correlation between ODC1 and OAZ1 (p < 0.019) measured in cancer cells. These correlations may function to evaluate the aggressiveness of human prostate cancer, and assist patients and clinicians to select appropriate treatment strategies based on biological activities of individual tumors.
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PMID:Assessing prostate cancer growth with mRNA of spermine metabolic enzymes. 2021 59

CGP 48664A, a new S-adenosylmethionine decarboxylase inhibitor, blocks the production of spermidine and spermine, two polyamines that play critical roles in cellular proliferation. Under in vitro conditions, CGP 48664A produced cytostasis of the human prostate cancer cell lines LNCaP, LNCaP-LN3, PC-3M, and PC-3M-MM2 in a dose-dependent manner. This cytostasis was reversed by the addition of exogenous polyamines to the culture medium. LNCaP-LN3 cells or PC-3M-MM2 cells were implanted into the prostate of nude mice. Daily administration of CGP 48664A significantly inhibited tumor size and serum levels of prostate-specific antigen in mice implanted with LNCaP-LN3 cells. The therapeutic effect was related to the time the treatment was initiated, the volume of disease, and the length of treatment. CGP 48664A was not effective against the fast-growing PC-3M-MM2 tumor. These data suggest that to broaden its effectiveness, CGP 48664A should be combined with other cytoreductive agents.
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PMID:Systemic administration of 4-amidinoindanon-1-(2'-amidino)-hydrazone, a new inhibitor of s-adenosylmethionine decarboxylase, produces cytostasis of human prostate-cancer in athymic nude-mice. 2155 36