Effect of a bifunctional monoclonal antibody directed against a tumor marker and doxorubicin on the growth of epidermoid vulvar carcinoma grafted in athymic mice.
Even though the first monoclonal antibodies (MAbs) directed against tumor cells were produced 15 yr ago, the therapeutic application of immunoconjugates is still at the beginning. This is principally because of the enormous work that is required for the development of completely new therapeutic tools. An alternative could be to only use MAbs to improve conventional treatment such as chemotherapy. To this aim, a MAb directed against doxorubicin (DXR) was produced. DXR is an anthracycline antibiotic of which the clinical usefulness in cancer chemotherapy is limited by serious side effects, such as cardiomyopathy, bone marrow depression, and gastrointestinal tract mucositis. This toxicity was found to be reduced by treatment with the antidrug MAb, as shown by reduction in body weight loss and mortality of experimental mice. To improve the DXR therapeutic index, a bifunctional hybrid MAb (DOXER2), capable of simultaneously recognizing DXR and the epidermal growth factor (EGF) receptor, was produced. This reagent was found in vitro to increase the drug toxicity on the epidermoid carcinoma cell line A431, which overexpresses the EGF-R and, at the same time, to reduce DXR cytotoxicity on EGF-R negative cells. The effect of DOXER2 on the DXR biodistribution in vivo was also investigated. In mice previously injected ip with the DOXER2, the uptake of the drug, in comparison to the control group, was found to be reduced in the intestine and in myocardial tissue, and significantly increased in the tumor.(ABSTRACT TRUNCATED AT 250 WORDS)
Morelli
D
D
Chair of Immunology, School of Medicine, University of Milan, Italy.
Ménard
S
S
Pozzi
B
B
Balsari
A
A
Colnaghi
M I
MI
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000918:Antibody Specificity; D000931:Antidotes; D014408:Biomarkers, Tumor / Q000276:immunology*; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000628:therapy*; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D004317:Doxorubicin / Q000276:immunology*; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000276:immunology*; D005260:Female; D006825:Hybridomas / Q000276:immunology; D007267:Injections; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014846:Vulvar Neoplasms / Q000473:pathology / Q000628:therapy*
D000911:Antibodies, Monoclonal; D000931:Antidotes; D014408:Biomarkers, Tumor; D004317:Doxorubicin; D066246:ErbB Receptors