Studies with CWR22 xenografts in nude mice suggest that ZD1839 may have a role in the treatment of both androgen-dependent and androgen-independent human prostate cancer.
OBJECTIVE
These studies examined the effect of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 ("Iressa")(3) on CWR22 prostate tumors in nude mice. The effect of ZD1839 was also examined in combination with either bicalutamide ("Casodex") or cytotoxic agents against a hormone-dependent or -independent variant of CWR22, respectively.


METHODS
The xenografts were grown for 4-7 days, then tumor measurements were made and therapy initiated. ZD1839 and bicalutamide were given p.o. on a once-daily, 5-day schedule for 2 successive weeks. Carboplatin and paclitaxel were given every 3-4 days for a total of four doses. Measurements of tumor volume were made twice weekly during treatment and for 2 weeks after treatment. The effect of ZD1839 on EGFR function was assessed by Western blotting of EGFR and its phosphorylated form in CWR22 and variant tumors before and after treatment with this agent.


RESULTS
ZD1839 at its maximum tolerated dose (150 mg/kg) inhibited the growth of androgen-dependent CWR22 by 54%, and the growth of two variants with different degrees of androgen independence and androgen receptor gene expression (CWR22LD1 and CWR22RV1) by 76%. The effects of ZD1839 were similar to those recorded for phosphorylation of EGFR as determined by Western blotting. Coadministration of ZD1839 at its maximum tolerated dose markedly increased the antiproliferative action of the antiandrogen bicalutamide against CWR22LD1. In fact, combining ZD1839 with a suboptimal dose of bicalutamide was more effective than a higher dose of bicalutamide alone. Coadministration of ZD1839, which required a 2-3-fold attenuation of dose to avoid toxicity, also markedly increased the therapeutic activity of carboplatin and paclitaxel against CWR22RV1, bringing about regression to a degree not seen with either agent alone. Tumor-free mice were seen only with the combination of ZD1839 and paclitaxel.


CONCLUSIONS
The results obtained in these related and highly relevant models of human prostate cancer suggest that ZD1839 may have a role in enhancing existing treatments of androgen-dependent and -independent forms of this disease in patients.
Sirotnak
Francis M
FM
Program in Molecular Pharmacology and Therapeutics and Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. sirotnaf@mskcc.org
She
Yohung
Y
Lee
Fei
F
Chen
Jing
J
Scher
Howard I
HI
D000813:Anilides / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015153:Blotting, Western; D016190:Carboplatin / Q000008:administration & dosage; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000235:genetics; D009570:Nitriles; D017239:Paclitaxel / Q000008:administration & dosage; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011799:Quinazolines / Q000008:administration & dosage; D011944:Receptors, Androgen / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology; D014105:Tosyl Compounds; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D000813:Anilides; D009570:Nitriles; D011799:Quinazolines; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D013739:Testosterone; C053541:bicalutamide; D016190:Carboplatin; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D017239:Paclitaxel; D000077156:Gefitinib