Bone marrow toxicity of cyclophosphazenes is related to their structure and the treatment schedule

For three aziridinyl-substituted inorganic heterocycles belonging to the cyclophosphazene group, the tendency for cumulative bone marrow toxicity was studied in mice. In a one-day regimen, one of these drugs, gem-N3P3Az4Pyr2 (Az = aziridinyl, Pyr = pyrrolidinyl) (AZX), led to an increased death rate after a repeated injection, the number of bone marrow stem cells (CFUgm) being decreased 5 weeks after the second injection of this drug. In a four-day regimen two drugs, (NPAz2)2 NSOAz (Soaz) and AZX, led to an increased death rate after the second treatment course. In surviving animals leucocyte and thrombocyte counts were significantly lower in the second than in the first course. CFUgm counts were decreased for both drugs. For the third drug, trans-N3P3(Az)2(NHMe)4 (AZP), no evidence of cumulative bone marrow toxicity was demonstrated. It is suggested that whereas cytostatic activity of these compounds seems to be comparable, their tendency to cause cumulative marrow toxicity may vary.