Electron-microscopical studies were made on the effects of cytosine arabinoside (ara-C) upon mouse L1210 leukemic cells.
On the 5th day after an intraperitoneal innoculation of 10⁵viable cells suspended in saline, either a single injection of 160 to 320mg ara-C/kg. b. w. or 6 successive injections of 15mg ara-C/kg. b. w. each at 2 hours intervals were made intraperitoneally. Control mice received saline only. Ten minutes to 24 hours following the last injection of ara-C, cells were collected from ascites, fixed in aldehyde and/or osmium tetroxide and processed for ultrastructural observation. For the light microscopic observation, a drop of ascites was smeared on clean glass slides and stained by the routine Giemsa method.
The mitotic index of the leukemic cells, which was originally 3.3%, was markedly suppressed by an ara-C injection going down to 0 %, followed by a gradual recovery to 1.2 to 1.4%,24 to 48 hours following the last injection, while the cell size was not significantly changed.
In the case of a single injection of ara-C, no appreciable alterations were noted in the fine structures of the cells till 3 hours following injection, although thereafter karyorrhectic and karyolytic changes were observed, which seemed to be non-specific cell degeneration processes caused by a single large dose of ara-C.
In concomitance with the destruction of the cells a number of macrophages appeared. However, characteristic changes in the nuclear structures of the L1210 cells were observed immediately following 6 successive injections of ara-C. These changes included a lowering of electron density of the nuclear matrix and the disappearance of condensed chromatins, especially those lying close to the nuclear envelope. No changes were observed in the nucleolonema of the nucleolus.
These findings seemed to coincide fairly well with the current biochemical knowledge that ara-C primarily inhibits DNA synthesis.