Systemic treatment with tetra-O-methyl nordihydroguaiaretic acid suppresses the growth of human xenograft tumors.
OBJECTIVE
We have previously shown that the transcriptional inhibitor tetra-O-methyl nordihydroguaiaretic acid (M4N) induces growth arrest in tumor cells and exhibits tumoricidal activity when injected intratumorally into tumor cell explants in mice. The experiments reported here were designed to determine whether M(4)N can be given systemically and inhibit the growth of five different human xenograft tumors.


METHODS
Nude (nu/nu) mice bearing xenografts of each of five human tumor types (i.e., hepatocellular carcinoma, Hep 3B; prostate carcinoma, LNCaP; colorectal carcinoma, HT-29; breast carcinoma, MCF7; and erythroleukemia, K-562) were treated with M4N given i.v. or i.p. in a Cremophor EL-based solvent system or orally in a corn oil based diet. Tumors from the treated animals were measured weekly and analyzed for the expression of the Cdc2 and survivin genes, both previously shown to be down-regulated by M4N.


RESULTS
Systemic M4N treatment suppressed the in vivo growth of xenografts in each of the five human tumor types. Four of the five tumor models were particularly sensitive to M4N with tumor growth inhibitions (T/C values) of < or = 42%, whereas the fifth, HT-29, responded to a lesser extent (48.3%). Growth arrest and apoptosis in both the xenograft tumors and in the tumor cells grown in culture were accompanied by reductions in both Cdc2 and tumor-specific survivin gene expression. Pharmacokinetic analysis following oral and i.v. administration to ICR mice indicated an absolute bioavailability for oral M4N of approximately 88%. Minimal drug-related toxicity was observed.


CONCLUSIONS
These preclinical studies establish that when given systemically, M4N can safely and effectively inhibit the growth of human tumors in nude mice.
Park
Richard
R
Department of Biology, Johns Hopkins University, Baltimore, Maryland 21218-2685, USA.
Chang
Chih-Chuan
CC
Liang
Yu-Chuan
YC
Chung
Yousun
Y
Henry
Ryan A
RA
Lin
Elaine
E
Mold
David E
DE
Huang
Ru Chih C
RC
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D016203:CDC2 Protein Kinase / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007275:Injections, Intravenous; D020014:K562 Cells; D009637:Masoprocol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009363:Neoplasm Proteins; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077022:Survivin; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays / Q000379:methods
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D000077022:Survivin; C076852:terameprocol; D009637:Masoprocol; D016203:CDC2 Protein Kinase