## University of the Pacific Theses and Dissertations

1988

Dissertation

#### Degree Name

Doctor of Philosophy (Ph.D.)

#### Department

Pharmacy

James Blankenship

#### First Committee Member

Donald Y. Shirachi

Paul A. Richmond

David S. Fries

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.

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