Mediation of reduction of spontaneous and experimental pulmonary metastases by ricin A-chain immunotoxin 45-2D9-RTA with potentiation by systemic monensin in mice.
We developed a model to assess the therapeutic effects of the 45-2D9-ricin A-chain immunotoxin (RTA) on pulmonary metastases. The 45-2D9 mouse monoclonal antibody recognizes a Mr 74,000 glycoprotein highly expressed by rat fibroblasts transformed with the Kirsten sarcoma virus (transformed rat fibroblasts). These cells metastasize spontaneously and form lung colonies in nu/nu and irradiated BALB/c mice. Injection i.v. of 45-2D9-RTA specifically reduced formation of spontaneous pulmonary metastases and lung colonies originating from freshly disaggregated tumor cells or cultured cells. Antibody alone or mixed with unconjugated ricin A chain and an immunotoxin that recognizes a melanoma-associated antigen were ineffective. Unconjugated 45-2D9 antibody specifically blocked the 45-2D9-RTA activity in vivo. Administration of the lysosomotrophic agents ammonium chloride and chloroquine in vivo did not potentiate immunotoxin-mediated reduction in lung colonies although they were effective in vitro. Monensin potentiated 45-2D9-RTA activity in vitro and in vivo.
Roth
J A
JA
Department of Thoracic Surgery, University of Texas System Cancer Center, M.D. Anderson Hospital and Tumor Institute, Houston 77030.
Ames
R S
RS
Fry
K
K
Lee
H M
HM
Scannon
P J
PJ
D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D000951:Antigens, Neoplasm / Q000032:analysis; D002738:Chloroquine / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D000922:Immunotoxins / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000556:secondary* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008985:Monensin / Q000627:therapeutic use*; D012276:Ricin / Q000627:therapeutic use*
D000951:Antigens, Neoplasm; D000922:Immunotoxins; D000643:Ammonium Chloride; D002738:Chloroquine; D012276:Ricin; D008985:Monensin; D004121:Dimethyl Sulfoxide