A new drug delivery method of bispecific ligand-directed toxins, which reduces toxicity and promotes efficacy in a model of orthotopic pancreatic cancer.
OBJECTIVE
Biologicals targeting epidermal growth factor (EGF) and interleukin 13 receptors not only react with overexpressed markers on cancer cells but also react with receptors on normal cells. Because we developed novel bispecific ligand-directed toxins synthesized by cloning EGF and interleukin 13 on the same molecule with toxin, our objective was to determine whether we could block normal receptors while still targeting receptors overexpressed on cancer cells, thereby decreasing toxicity while maintaining efficacy.


METHODS
A method, toxicity blocking (ToxBloc), was developed in which a bolus intraperitoneal dose of recombinant EGF13 (without toxin) was given to mice approximately 15 to 20 minutes before DTEGF13. Experiments were then performed to determine whether the maximal tolerated dose (MTD) was reduced and whether we were still able to eliminate progression of aggressive human, metastatic, pancreatic cancer induced by orthotopic injection (OT) in nude mice.


RESULTS
ToxBloc permitted us to safely exceed the DTEGF13 maximal tolerated dose by 15-fold. This approach permitted repetitive high dosing with the bispecific ligand-directed toxin resulting in tumor regression (P < 0.01). Tumor effects were documented using a tumor imaging model in which OT tumor growth was monitored noninvasively in real time. ToxBloc was selective because other bispecific peptides did not block.


CONCLUSIONS
ToxBloc represents a new method of drug delivery and a potential solution to the problem of toxicity.
Oh
Seunguk
S
Therapeutic Radiology and daggerSurgery, University of Minnesota Cancer Center, Minneapolis, MN 55455, USA.
Stish
Brad J
BJ
Vickers
Selwyn M
SM
Buchsbaum
Donald J
DJ
Saluja
Ashok K
AK
Vallera
Daniel A
DA
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004167:Diphtheria Toxin / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D004167:Diphtheria Toxin; D018793:Interleukin-13; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D004815:Epidermal Growth Factor