Gene expression correlating with response to paclitaxel in ovarian carcinoma xenografts.
We have investigated gene expression profiles of human ovarian carcinomas in vivo during Taxol(R) (paclitaxel) treatment and observed a difference in expression. Nude mice bearing 1A9 or 1A9PTX22 xenografts were given 60 mg/kg of paclitaxel. Therapeutic efficacy was achieved for 1A9, while 1A9PTX22 did not respond. Tumor tissues harvested 4 and 24 h after treatment were evaluated by cDNA microarray against untreated tumors. Paclitaxel caused the modulation of more genes in 1A9 than in 1A9PTX22 tumors, in accordance to their therapeutic response. Most gene expression alterations were detected 24 h after paclitaxel administration and affected genes involved in various biological functions including cell cycle regulation and cell proliferation (CDC2, CDKN1A, PLAB, and TOP2A), apoptosis (BNIP3 and PIG8), signal transduction and transcriptional regulation (ARF1, ATF2, FOS, GNA11, HDAC3, MADH2, SLUG, and SPRY4), fatty acid biosynthesis and sterol metabolism (FDPS, IDI1, LIPA, and SC5D), and IFN-mediated signaling (G1P3, IFI16, IFI27, IFITM1, and ISG15). The modulation of two representative genes, CDKN1A and TOP2A, was validated by Northern analyses on a panel of seven ovarian carcinoma xenograft models undergoing treatment with paclitaxel. We found that the changes in expression level of these genes was strictly associated with the responsiveness to paclitaxel. Our study shows the feasibility of obtaining gene expression profiles of xenografted tumor models as a result of drug exposure. This in turn might provide insights related to the drugs' action in vivo that will anticipate the response to treatment manifested by tumors and could be the basis for novel approaches to molecular pharmacodynamics.
Mario Negri Institute for Pharmacological Research, Bergamo and Milan, Italy.
Maria Rosa
MR
Bani
Maria Ines
MI
Nicoletti
Nawal W
NW
Alkharouf
Carmen
C
Ghilardi
David
D
Petersen
Eugenio
E
Erba
Edward A
EA
Sausville
Edison T
ET
Liu
Raffaella
R
Giavazzi
D000818:Animals; D015152:Blotting, Northern; D002453:Cell Cycle; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D012333:RNA, Messenger; D017239:Paclitaxel