WEHI-3B D+ Y1 leukemia cells as a model system to assess the induction of differentiation in vivo.
An in vivo model system for assaying the induction of differentiation by therapeutic agents was developed using WEHI-3B D+ Y1 myelomonocytic leukemia cells in BALB/c mice, which exhibit characteristics analogous to those of human acute non-lymphocytic leukemia. An integrated copy of the non-mammalian 3'-aminoglycoside phosphotransferase gene in WEHI-3B D+ Y1 cells permitted the unambiguous identification of these leukemia cells in vivo by in situ hybridization. The administration of aclacinomycin A to BALB/c mice bearing this leukemia produced an increase in survival time. In situ analyses of peritoneal cells obtained from anthracycline-treated animals supported the concept that the increase in life-span was due in part to the induced maturation of WEHI-3B D+ Y1 cells to more mature granulocytic elements. This action was accompanied by an order of magnitude decrease, relative to vehicle-treated animals, in the peritoneal leukemic cell burden. The schedule and dosage of the anthracycline antibiotic that produced the maximum prolongation of life had no effect on peripheral platelet levels or packed red cell volume. Elevated white blood cell levels were observed in leukemia-bearing mice; these increases were reversed in animals receiving 2 mg/kg of aclacinomycin A and reached control levels by day 8. Treatment with aclacinomycin A had no effect on body weight, or femoral or splenic cellularity. Increased numbers of granulocyte-macrophage colony forming units were observed in leukemia-bearing animals. Leukemia-bearing mice receiving aclacinomycin A decreased these stem cell levels to that of drug-treated non-leukemia bearing animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Gamba-Vitalo
C
C
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510.
Carman
M D
MD
Sartorelli
A C
AC
D015250:Aclarubicin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D006410:Hematopoiesis / Q000187:drug effects*; D019868:Kanamycin Kinase; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009693:Nucleic Acid Hybridization; D010770:Phosphotransferases / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D014162:Transfection
D000970:Antineoplastic Agents; D012333:RNA, Messenger; C011157:aclacinomycins; D015250:Aclarubicin; D010770:Phosphotransferases; D019868:Kanamycin Kinase