title: Monoclonal antibody Po66 uptake by human lung tumours implanted in nude mice: effect of co-administration with doxorubicin.
abstract: The efficacy of radioimmunotherapy of tumours with radiolabelled monoclonal antibodies (MAbs) depends on the amount of antibody taken up by the tumour and on its intratumoral distribution. In the case of MAbs directed against intracellular antigens, increasing the permeability of the cytoplasmic membrane may augment the bioavailability of the antigen for the antibody. This raises the question whether the induction of tumour necrosis by chemotherapy can enhance the tumour uptake of radiolabelled monoclonal antibodies. In this work, the effect of doxorubicin on the biodistribution of Po66, an MAb directed against an intracellular antigen, was studied in nude mice grafted with the human non-small-cell lung carcinoma cell line SK-MES-1. After injection on day 0 of 125I-labelled Po66, tumour radioactivity increased up to days 3-5, and then remained unchanged to day 14. The combined administration of 125I-labelled Po66 with 8 mg kg-1 doxorubicin, in two doses separated by 7 days, doubled the radioactivity retained by the tumour. Histological and historadiographic analysis showed, however, that the drug induced cellular damage. In the absence of doxorubicin, the accumulation of Po66 was restricted to some necrotic areas, whereas with doxorubicin the necrosis was more extensive and the antibody more evenly distributed. These results suggest that chemotherapy and immunoradiotherapy combined would enhance tumour uptake of radioisotope and promote more homogenous distribution of the radiolabelled MAb. This would promote eradication of the remaining drug-resistant cells in tumours.
authors.affiliation: Service de Pneumologie, Centre Hospitalier Régional et Universitaire, Hôpital Pontchaillou, Rennes, France.
authors.forename: B
authors.initials: B
authors.lastname: Desrues
authors.forename: H
authors.initials: H
authors.lastname: Léna
authors.forename: F
authors.initials: F
authors.lastname: Brichory
authors.forename: M P
authors.initials: MP
authors.lastname: Ramée
authors.forename: L
authors.initials: L
authors.lastname: Toujas
authors.forename: P
authors.initials: P
authors.lastname: Delaval
authors.forename: L
authors.initials: L
authors.lastname: Dazord
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000532:radiotherapy; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D007424:Intracellular Fluid / Q000276:immunology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000532:radiotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011059:Polonium / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016499:Radioimmunotherapy; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D018796:Immunoconjugates; D007074:Immunoglobulin G; D004317:Doxorubicin; D011059:Polonium