Increased survival and multilineage hematopoietic protection from delayed and severe myelosuppressive effects of a nitrosourea with recombinant interleukin-11.

Abstract

The chloroethylnitrosoureas, such as 1,3-bis(2-chloroethyl)-1-nitrosourea, are alkylating agents which are thought to exert antitumor activity by initiating lethal DNA interstrand cross-links. Although nitrosoureas are among the most active agents against childhood and adult gliomas, the utility of this class of agents has been limited by severe and cumulative myelosuppression, which can be fatal. Nitrosourea-induced myelosuppression in humans is delayed and may continue after withdrawal of the agent. We have developed a murine model which mimics the delayed and cumulative myelosuppression seen in humans receiving nitrosoureas. In this model, we demonstrate that interleukin-11, a stromal-derived hematopoietic growth factor with pleiotropic effects in a number of preclinical ablation models, markedly diminishes nitrosourea-induced pancytopenia and leads to a significant reduction in chemotherapy-related mortality. These data suggest that interleukin-11 could allow significant dose intensification in the treatment of tumors which are nitrosourea sensitive.