Date of Award

1988

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Pharmacy

First Advisor

James Blankenship

First Committee Member

Donald Y. Shirachi

Second Committee Member

Paul A. Richmond

Third Committee Member

David S. Fries

Fourth Committee Member

Marvin H. Malone

Abstract

The phenylhydrazine-induced erythropoietic mouse spleen is used as a model system to demonstrate the relationship between tissue growth and polyamine metabolism. Phenylhydrazine produced significant changes in spleen weights, hematocrits and reticulocyte counts in Swiss-Webster mice. The average spleen weight went up from a control of 155 mg to 875 mg at 96 hours after phenylhydrazine administration, while a 49% reduction in the value of hematocrit was observed at 72 hours. Reticulocyte counts in peripheral blood went from 0.8 to 58% at 168 hours after treatment with phenylhydrazine. Phenylhydrazine at a dose of 40 mg/kg produced significant increases in the levels of putrescine, spermidine and spermine with maxima reached within 72 hours. The levels of N$\sp1$-acetylspermidine reached a maximum of 2.7-fold compared to control at 96 hours. When the dose of phenylhydrazine was increased to 120 mg/kg, peak levels of acetylated polyamines were reached within 96 hours at which time N$\sp1$-acetylspermidine levels rose to 2.9-fold and N$\sp8$-acetylspermidine levels went from not detectable to detectable levels. the levels of putrescine, spermidine and spermine reached maxima at 96 hours of 289, 1248 and 934 nmoles/g, respectively. DL-$\alpha$-difluoromethylornithine hydrochloride monohydrate (DFMO) inhibited the increases in putrescine levels and potentiated the increases in spermine levels induced by phenylhydrazine, while 7-(N-(3-aminopropyl)amino) heptan-2-one.2HCl (APAH) induced significant increases in the levels of N$\sp8$-acetylspermidine. APAH potentiated the increases in spleen weights induced by phenylhydrazine.

Pages

103

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