Cytotoxicity of gelonin and its conjugates with antibodies is determined by the extent of their endocytosis.
Conjugates of the single-chain ribosome-inactivating protein gelonin with ligands that bind to cell surface molecules vary greatly in their cytotoxicity. Conjugates that are not endocytosed after binding to cells exhibit low cytotoxicity similar to that of free gelonin, while conjugates that are endocytosed demonstrate enhanced cytotoxicity relative to free gelonin. However, the number of internalized gelonin molecules needed to intoxicate cells to the same degree has been found to be similar for all conjugates and for free gelonin. The intracellular concentration of gelonin has to be between 2,000-10,000 molecules/cells to achieve a surviving fraction of 0.37. Our studies revealed the presence of three distinct categories of cell surface molecules, those that are efficient in mediating endocytosis of immunotoxins, those that are only moderately efficient, and those that seem not to cause internalization of bound immunotoxins.
Goldmacher
V S
VS
Division of Tumor Immunology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115.
Scott
C F
CF
Lambert
J M
JM
McIntyre
G D
GD
Blättler
W A
WA
Collnhson
A R
AR
Stewart
J K
JK
Chong
L D
LD
Cook
S
S
Slayter
H S
HS
D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology; D001345:Autoradiography; D002460:Cell Line; D004705:Endocytosis; D006801:Humans; D000922:Immunotoxins / Q000633:toxicity*; D051379:Mice; D008854:Microscopy, Electron; D015260:Neprilysin; D010940:Plant Proteins / Q000633:toxicity*; D011500:Protein Synthesis Inhibitors / Q000633:toxicity*; D011990:Receptors, Transferrin / Q000276:immunology; D054789:Ribosome Inactivating Proteins, Type 1; D013329:Structure-Activity Relationship
D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D000922:Immunotoxins; D010940:Plant Proteins; D011500:Protein Synthesis Inhibitors; D011990:Receptors, Transferrin; D054789:Ribosome Inactivating Proteins, Type 1; C025674:GEL protein, Gelonium multiflorum; D015260:Neprilysin