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

Cancer Chemother Pharmacol. 1995;35(5):364-70. doi: 10.1007/s002800050248.

Abstract

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.

Publication types

  • Comparative Study

MeSH terms

  • 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

Substances

  • Antineoplastic Agents
  • Monosaccharide Transport Proteins
  • Phosphoramide Mustards
  • beta-D-glucosylisophosphoramide mustard
  • isophosphamide mustard
  • Phlorhizin
  • Glucose
  • Ifosfamide