D-19575--a sugar-linked isophosphoramide mustard derivative exploiting transmembrane glucose transport.
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.
Pohl
J
J
Asta Medica AG, Frankfurt/Main, Germany.
Bertram
B
B
Hilgard
P
P
Nowrousian
M R
MR
Stüben
J
J
Wiessler
M
M
D000042:Absorption / Q000187:drug effects; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004195:Disease Models, Animal; D004341:Drug Evaluation; D004361:Drug Tolerance; D005260:Female; D005947:Glucose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D007069:Ifosfamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000187:drug effects*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010695:Phlorhizin / Q000494:pharmacology; D010752:Phosphoramide Mustards; D051381:Rats; D017207:Rats, Sprague-Dawley; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009004:Monosaccharide Transport Proteins; D010752:Phosphoramide Mustards; C092028:beta-D-glucosylisophosphoramide mustard; C027061:isophosphamide mustard; D010695:Phlorhizin; D005947:Glucose; D007069:Ifosfamide