D-19575--a sugar-linked isophosphoramide mustard derivative exploiting transmembrane glucose transport

• Published in: Cancer chemotherapy and pharmacology Vol. 35; no. 5; p. 364
• Main Authors: Pohl, J, Bertram, B, Hilgard, P, Nowrousian, M R, Stüben, J, Wiessler, M
• Format: Journal Article
• Language: English
• Published: Germany 01.01.1995
• Subjects: Absorption - drug effects; Administration, Oral; Animals; Antineoplastic Agents - adverse effects; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Bone Marrow - drug effects; Bone Marrow Cells; Cells, Cultured; Colony-Forming Units Assay; Disease Models, Animal; Drug Evaluation; Drug Tolerance; Female; Glucose - administration & dosage; Glucose - analogs & derivatives; Glucose - chemical synthesis; Glucose - metabolism; Glucose - pharmacology; Glucose - therapeutic use; Ifosfamide - administration & dosage; Ifosfamide - analogs & derivatives; Ifosfamide - chemical synthesis; Ifosfamide - chemistry; Ifosfamide - metabolism; Ifosfamide - pharmacology; Ifosfamide - therapeutic use; Kidney - drug effects; Leukocytes - drug effects; Mice; Monosaccharide Transport Proteins - drug effects; Neoplasm Transplantation; Neoplasms, Experimental - drug therapy; Phlorhizin - pharmacology; Phosphoramide Mustards; Rats; Rats, Sprague-Dawley; Specific Pathogen-Free Organisms; Spleen - cytology; Spleen - drug effects; Tumor Cells, Cultured
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s002800050248

D-19575 is a glucose derivative of ifosfamide mustard with a broad spectrum of antitumor activity in animal models. In comparison with ifosfamide, D-19575 is less toxic and is better tolerated by tumor-bearing animals, achieving a better therapeutic efficacy. D-19575 is directly cytotoxic in vitro--in contrast to ifosfamide--and it is possible to modulate this cytotoxicity by inhibition of transmembrane glucose transporters. Correspondingly, renal reabsorption of filtered D-19575 could be blocked by pre- and cotreatment with phlorizin, resulting in a higher urinary excretion of the unchanged drug. The toxicity to white blood cells, colony-forming units (CFU-C), and spleen-cell colony-forming units (CFU-S) is considerably lower for D-19575 as compared with ifosfamide. In conclusion, D-19575 is a new alkylating cytotoxic agent with increased antitumor selectivity, probably caused by an active transmembrane transport mechanism.