The level of DNA interstrand crosslinking in bone marrow parallels the extent of myelosuppression in mice treated with four chloroethylnitrosoureas
The effects of dose and schedule of administration of either 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or 1-(2-hydroxyethyl)-3-(2-chloroethyl)-3-nitrosourea (HECNU) were compared in terms of induction of DNA damage in the bone marrow of male C6B3F1 mice or in the inhibition of two stem cell lines contained therein. At equimolar doses HECNU induced a 3- to 40-fold deeper nadir of proliferation of both stem cell lines compared to BCNU, but subsequently a 2- to 30-fold quicker recovery of these lines was observed. An enhancement of myelotoxicity was only found following injections with intervals of 1 week. Myelosuppression was almost twice as great, when six instead of three weekly injections of 50 μmol/kg were given. When, however, sufficient time was allowed larger doses of drug was tolerated at the level of the bone marrow stem cell. The maximum inhibition of pluripotent- and granulocyte-committed stem cells following HECNU was paralleled by higher amounts of DNA-DNA interstrand crosslinks in the entire bone marrow compared to BCNU. During the inital stages, the degree of myelosupression did, to some extent, parallel the number of DNA-DNA interstrand crosslinks induced in the bone marrow as a whole, but this relation was lost after the initial period.