6-[Bis(2-chloroethyl)amino]-6-deoxygalactopyranose hydrochloride (C6-galactose mustard), a new alkylating agent with reduced bone marrow toxicity.
We have previously reported that chloroethyl nitrosourea and nitrogen mustard bone marrow toxicity can be selectively reduced by placement of the cytotoxic group on specific positions of a glucose molecule. We have now synthesized and evaluated a new drug in which the mustard cytotoxic group is attached to the carbon-6 position of galactose (C6-GLM). C6-GLM, administered i.p. as a single 10% lethal dose of 15.5 mg/kg, produced a 121% increase in life span (ILS) in mice bearing the ascitic P388 leukemia, compared to a 60% ILS with a 10% lethal dose of nitrogen mustard (P less than 0.01). A single p.o. dose of C6-GLM, 16 mg/kg, produced an ILS of 58%. Against i.p.-implanted B-16 melanoma, i.p. C6-GLM produced a 56% ILS compared to 30% with an equitoxic dose of nitrogen mustard (P less than 0.01). The activity of the two drugs for Ehrlich ascites was comparable, with 60% survivors with the galactose mustard. A single 10% lethal dose of C6-GLM reduced the white blood cells to 74% of control; circulating granulocytes remained at 91% of initial values. With nitrogen mustard, the nadir white blood cell count was 57% of control with an absolute granulocyte count of 70% of initial values (P less than 0.01). The toxicity of melphalan was considerably greater, with a lower and more protracted while blood cell nadir and an absolute neutrophil count nadir of 49% of control. These findings paralleled the relative decrements in bone marrow DNA synthesis produced by the three drugs. Measurement of human bone marrow granulocyte-macrophage colony-forming units, following in vitro exposure to graded concentrations of the three mustards, confirmed the bone marrow sparing properties of C6-GLM. At the highest concentration, 1 X 10(-2) mM, the latter drug produced only a 33% reduction in colonies compared to a 75% reduction with nitrogen mustard and a virtual elimination of activity of colony-forming units with melphalan. The demonstration of antitumor activity, at least equivalent to nitrogen mustard, without the necessity of significant bone marrow toxicity supports the development of C6-GLM for clinical trials in humans.
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology*; D004261:DNA Replication / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005260:Female; D005688:Galactosamine / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D007941:Leukemia P388 / Q000188:drug therapy*; D007942:Leukemia, Experimental / Q000188:drug therapy*; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008466:Mechlorethamine / Q000633:toxicity; D008558:Melphalan / Q000633:toxicity; D051379:Mice; D008811:Mice, Inbred DBA; D009504:Neutrophils / Q000166:cytology; D013329:Structure-Activity Relationship
C050475:C6-galactose mustard; D008466:Mechlorethamine; D005688:Galactosamine; D008558:Melphalan