Date of Award

9-1976

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Biochemistry

Supervisor

B.L. Hillcoat

Abstract

Recent evidence suggests that phosphorodiamidic acid is formed from cyclophosphamide in vivo and in vitro and may be the active form of this drug.

We have studied the effect of phosphorodiamidit acid and cyclophosphamide on the growth of the mouse leukemic cell lines LM4 and LS2 in culture. On this basis, phosphorodiamidic acid was at least 100 times more potent than cyclophosphamide in inhibiting growth. It also produced enlargement of cells, an effect not seen with cyclophosphamide.

Although two metabolites of cyclophosphamide, phosphorodiamidic acid and acrolein were isolated and identified, attempts to measure these metabolites accurately were unsuccessful. Consequently the stoichiometry of the conversion could not be determined.

Phosphorodiamidic acid significantly increased the amount of cross-linked DNA after incubation with intact LM4 cells or isolated nuclei from these cells. Cyclophosphamide had a similar effect only in the isolated nuclei.

These findings strengthen the proposed role of phosphorodiamidic acid as the active metabolite of cyclophosphamide.


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