Recent advances in cancer research: drug targeting without the use of monoclonal antibodies.
Cancer research in drug targeting has focused on the use of monoclonal antibody conjugates of drugs. This paper discusses the use of ligand conjugates of drugs to deliver to receptors on cancer cells. We have used transferrin coupled to adriamycin, and report these conjugates specifically bind and kill cancer cells in culture. Our studies of the mechanism show targeted plasma membranes are compromised for NADH ferricyanide reduction, and targeted cells lose diferric transferrin reductase activity. These results indicate that the binding of transferrin-adriamycin conjugates to transferrin receptors on either isolated plasma membranes or viable tumor cells causes an inhibition of redox reactions that are essential for growth. Since transferrin receptors are endocytosable, ligand-drug conjugates also are delivered to the interior of targeted cells where other mechanisms of killing can be employed. This novel method of drug delivery circumvents the need for monoclonal antibodies, and more investigation of the system may allow a controlled clinical study of its effectiveness.
Faulk
W P
WP
Center for Reproduction and Transplantation Immunology, Methodist Hospital of Indiana, Indianapolis 46202.
Harats
H
H
McIntyre
J A
JA
Berczi
A
A
Sun
I L
IL
Crane
F L
FL
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004273:DNA, Neoplasm / Q000187:drug effects; D004317:Doxorubicin / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D004337:Drug Carriers; D006801:Humans; D008024:Ligands; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D011990:Receptors, Transferrin / Q000378:metabolism*; D014168:Transferrin / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D004337:Drug Carriers; D008024:Ligands; D011990:Receptors, Transferrin; D014168:Transferrin; D004317:Doxorubicin