Improved anti-tumor activity and safety of interleukin-13 receptor targeted cytotoxin by systemic continuous administration in head and neck cancer xenograft model.
BACKGROUND
IL-13 receptor (IL-13R) targeted cytotoxin, IL13-PE38QQR, has been shown to have very potent anti-tumor activity to IL-13R-expressing head and neck tumor cells in vitro and in vivo. However, its effect is limited in aggressive tumors. To further improve the anti-tumor activity and safety of IL-13 cytotoxin, we employed continuous infusion technique in animal model of head and neck cancer.


METHODS
We surgically implanted continuous infusion (CI) pump intraperitoneally that released drug for 7 days, and its anti-tumor effect was evaluated. A comparison was made for antitumor activity and safety with intravenously (IV) administered IL-13 cytotoxin in a head and neck (KCCT873 and HN12) subcutaneous (SC) xenograft tumor models in nude mice. Vital organ toxicities were assessed by histologic examinations and blood serum chemistry analyses.


RESULTS
The 50 or 75 micro g/kg/day for 7 days of IL-13 cytotoxin either by IV or CI administration did not show any difference in safety or anti-tumor activity. IV administration of 150 or 200 micro g/kg/day of IL-13 cytotoxin for 7 days was lethal to nude mice, whereas 200 micro g/kg/day X 7 days of CI administration was highly effective in the regression of established tumors without any toxicities. Additionally, CI administration of IL-13 cytotoxin (200 micro g/kg/day) showed growth inhibition of larger HN12 tumors in nude mice.


CONCLUSIONS
With a CI schedule, IL-13 cytotoxin can be systemically administrated at approximately twice the dose otherwise given by daily IV bolus administration.
Kawakami
Koji
K
Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Husain
Syed R
SR
Kawakami
Mariko
M
Puri
Raj K
RK
D036002:ADP Ribose Transferases / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D005098:Exotoxins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007263:Infusions, Parenteral; D007275:Injections, Intravenous; D018793:Interleukin-13 / Q000008:administration & dosage / Q000494:pharmacology*; D053661:Interleukin-13 Receptor alpha1 Subunit; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D018123:Receptors, Interleukin / Q000187:drug effects*; D053660:Receptors, Interleukin-13; D014183:Transplantation, Heterologous; D037521:Virulence Factors / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000970:Antineoplastic Agents; D001427:Bacterial Toxins; D005098:Exotoxins; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C508181:IL13RA1 protein, human; C508183:Il13ra1 protein, mouse