Antigrowth Effect of Some Inhibitors of Polyamine Synthesis on Transplantable Prostate Cancer

Dunzendorfer, U; Relyea, Noël M.; Kleinert, Edward L.; Balis, M. Earl; Whitmore, Willet F.

doi:10.1159/000225692

Cited by 23 publications

(11 citation statements)

References 10 publications

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“…This occurred even in patients in whom the DFMO was clearly acting effec tively as an ODC inhibitor, as evidenced by the decline achieved in the cellular po lyamine levels during the pretreatment period. Administration of MGBG to animals promotes large increases in the putrescine levels of rat intestinal mucosa [30], mouse brain [14], ventral prostate [18], spleens of LI210 leukemia-bearing mice [11], and transplantable prostate cancer [7], How ever, in contrast to the present findings in humans, all of the animal studies, except that done with ventral prostate, found that MGBG promoted a decrease or no change in tissue spermidine levels and little change in spermine levels. Administration of MGBG to animals promotes an in crease in tissue activities of both ODC [7,9,12,14,18,30] and AMeDC [9,15,18,27,30] providing a potential explanation for the increased cellular polyamines noted in the present study.…”

Section: Discussionmentioning

confidence: 99%

Polyamines Increase in Human Peripheral Blood and Bone Marrow Mononuclear Cells following Administration of Methylglyoxal bis(guanylhydrazone)

Maddox¹,

Keating

Freireich³

et al. 1988

Chemotherapy

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Eight patients who had refractory leukemia and 1 patient with refractory multiple myeloma were treated with the polyamine biosynthesis inhibitors methylgloxal bis(guanylhydrazone) (MGBG) and difluoromethylornithine (DFMO). After the first dose of MGBG there was an increase in polyamine content in the mononuclear cells of both the peripheral blood and the bone marrow despite the administration of DFMO in all patients with leukemia. Putrescine levels increased in the mononuclear cells of all patients, cellular spermidine levels increased in 4 and cellular spermine levels increased in 5 patients. The cellular polyamine levels remained elevated above the pretreatment levels for up to 1 week in some patients. Subsequent treatment with MGBG, administered after 1–2 weeks of DFMO treatment, also promoted increases in monouclear cell polyamine concentrations. Since enhanced tumor cell uptake of MGBG after DFMO priming is hypothesized to be dependent on a decrease in cellular polyamine levels, the increase in cellular polyamines after MGBG has important implications for the scheduling of this drug combination. From these observations, withholding MGBG until DFMO treatment has produced a decrease in tumor cell polyamine concentrations would be the schedule most likely to enhance the uptake of MGBG.

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Section: Discussionmentioning

confidence: 99%

Polyamines Increase in Human Peripheral Blood and Bone Marrow Mononuclear Cells following Administration of Methylglyoxal bis(guanylhydrazone)

Maddox¹,

Keating

Freireich³

et al. 1988

Chemotherapy

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“…Even though testosterone-induced growth of rat ventral prostate and seminal vesicle appears to respond poorly to the antiproliferative action of polyamine anti-metabolities (with the possible exception of difluoromethylornithine-induced diminution of prostatic secretion), a few reports indicate that experimental tumours of prostatic origin may be especially sensitive to the combined action of difluoromethylornithine and methylglyoxal bis(guanylhydrazone) when transplanted subcutaneously (Dunzendorfer et al, 1983;Herr & Kleinert, 1983). Of special interest is the report by Herr & Kleinert (1983) showing that the toxicity of methylglyoxal bis(guanylhydrazone) can be dramatically decreased, without lowering the dose, by combining the drug with difluoromethylornithine.…”

Section: Discussionmentioning

confidence: 99%

“…Growth of prostatic cancer cells transplanted subcutaneously in rats was inhibited by combined treatment with these two polyamine anti-metabolites (Dunzendorfer et al, 1983;Herr & Kleinert, 1983 for 20min in the cold. The enzyme activities and the content of difluoromethylornithine were assayed in the supernatant fraction.…”

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confidence: 99%

Differential effects of 2-difluoromethylornithine and methylglyoxal bis(guanylhydrazone) on the testosterone-induced growth of ventral prostate and seminal vesicles of castrated rats

Käpyaho¹,

Kallio²,

Jänne³

1984

Biochemical Journal

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1. 2-Difluoromethylornithine totally prevented any increases in putrescine and spermidine concentrations in the ventral prostate of castrated rats during a 6-day testosterone treatment. Prostatic ornithine decarboxylase activity was inhibited by 80%, whereas S-adenosylmethionine decarboxylase was stimulated by more than 9-fold. 2. In seminal vesicle, the inhibition of putrescine and spermidine accumulation, as well as ofornithine decarboxylase activity, was only minimal, and no stimulation of S-adenosylmethionine decarboxylase was observed. 3. Administration of methylglyoxal bis(guanylhydrazone) to castrated androgen-treated rats resulted in a marked increase in concentrations of all prostatic polyamines. Prostatic ornithine decarboxylase activity was nearly 2 times and adenosylmethionine decarboxylase activity 9 times higher than that of the testosterone-treated animals. 4. In contrast with ventral prostate, methylglyoxal bis(guanylhydrazone) treatment inhibited moderately the accumulation of spermidine and spermine in seminal vesicle, although both ornithine decarboxylase and S-adenosylmethionine decarboxylase activities were stimulated. 5. Difluoromethylornithine inhibited significantly the weight gain of ventral prostate, but methylglyoxal bis(guanylhydrazone) produced a substantial increase in prostatic weight. These changes were largely due to the fact that the volume of prostatic secretion was greatly decreased by difluoromethylornithine, whereas methylglyoxal bis(guanylhydrazone) increased the amount of secretion. 6. Treatment with difluoromethylornithine strikingly increased the methylglyoxal bis(guanylhydrazone) content of both ventral prostate and seminal vesicle, but even under these conditions the drug concentration remained low in comparison with other tissues. 7. The results indicate that a combined use of these two polyamine anti-metabolites does not necessarily result in a synergistic growth inhibition of the androgen-induced growth of male accessory sexual glands.

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“…In den Tumoren wurden die Polyamine Putrescin und Spermidin be stimmt. Daneben wurden die enzymatischen Aktivitä ten der ODC und der SAMDC in modifizierter Form, wie mitgeteilt, ermittelt [16,17] …”

Section: Materials Und Methodikunclassified

“…Spermin [1,2,9], Die Aktivität der ODC ist in Tumoren gesteigert, und erhöhte Konzentrationen von Putrescin und Spermidin sind bei allen bisher untersuchten Tumorgeweben nachgewiesen worden. Dabei ist regelmässig festzustellen, dass die Wachstumsrate von Tumoren von der intrazellulären Polyaminkonzentration abhängt [10][11][12][13], Die Konzentrationen von Putrescin, Sper midin und Spermin im Gewebe der Ratten prostata sind signifikant höher als in allen anderen Organen, und es ist bekannt, dass Polyamine in hoher Konzentration im Sperma Vorkommen und dort nutritive wie stabilisierende Funktionen ausüben [14], Die Konzentrationen der Polyamine im mensch lichen Prostatagewebe sowie die 24-StundenAusscheidung von Polyaminen bei Patienten mit Prostatakarzinomen stimmen mit den bisherigen Ergebnissen über Polyamine und Tumorstoffwechsel überein [14,15] [16,17], Die begrenzten therapeutischen Möglich keiten des metastasierenden hormonrefraktä ren Prostatakarzinoms bei Männern unter 60 Jahren lassen eine präklinische Untersu chung mit Inhibitoren der Omithindecarboxylase durch Alpha-Difluoromethylomithin (DFMO) und S-Adenosylmethionindecarboxylase durch Methylglyoxal-bis-guanylhydrazon (MGBG) als wichtig erscheinen.…”

unclassified

Therapie des Prostatakarzinoms mit Polyaminsyntheseinhibitoren

Dunzendorfer¹

1982

Urol Int

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The therapeutic concept of irreversible inhibition of both ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC) by alpha-difluoromethylornithine (DFMO) and methylglyoxal bis-guanylhydrazone (MGBG) is based on pathologic activities of these enzymes in tumor tissue. The polyamines putrescine, spermidine and spermine are measured in highest concentration in the prostate of both men and animals, with a significant increase of spermine in benign hyperplasia of the prostate. Patients with metastatic cancer of the prostate have elevated putrescine levels in the 24-hour urine. Treatment with 3 or 1% DFMO or 11 mg/kg MGBG in transplantable human and experimental cancer of the prostate demonstrated a significant anti-growth effect. A combination of DFMO and MGBG is tumor-destructive. The combination of 1% DFMO and 11 mg/kg MGBG distinctly reduces the activity of ODC and SAMDC and significantly lowers the levels of putrescine, spermidine and spermine in the tumor.

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Antigrowth Effect of Some Inhibitors of Polyamine Synthesis on Transplantable Prostate Cancer

Cited by 23 publications

References 10 publications

Polyamines Increase in Human Peripheral Blood and Bone Marrow Mononuclear Cells following Administration of Methylglyoxal bis(guanylhydrazone)

Polyamines Increase in Human Peripheral Blood and Bone Marrow Mononuclear Cells following Administration of Methylglyoxal bis(guanylhydrazone)

Differential effects of 2-difluoromethylornithine and methylglyoxal bis(guanylhydrazone) on the testosterone-induced growth of ventral prostate and seminal vesicles of castrated rats

Therapie des Prostatakarzinoms mit Polyaminsyntheseinhibitoren

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