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Murine Model for Non-invasive Imaging to Detect and Monitor Ovarian Cancer Recurrence
Published on: November 2, 2014
Gene expression correlating with response to paclitaxel in ovarian carcinoma xenografts
Maria Rosa Bani1, Maria Ines Nicoletti, Nawal W Alkharouf
1Mario Negri Institute for Pharmacological Research, Bergamo and Milan, Italy.
Abstract:
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.
Insights
Gene expression profiling reveals paclitaxel (Taxol) treatment alters gene expression in ovarian cancer xenografts. Responding tumors showed more significant gene modulation, identifying key genes linked to treatment efficacy and providing insights into molecular pharmacodynamics.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Paclitaxel (Taxol) is a key chemotherapy agent for ovarian cancer.
- Understanding drug response at the molecular level is crucial for improving treatment efficacy.
- Gene expression profiling offers a method to investigate drug-induced molecular changes in tumors.
Purpose of the Study:
- To investigate gene expression profiles in ovarian cancer xenografts during paclitaxel treatment.
- To correlate gene expression changes with therapeutic response to paclitaxel.
- To explore the potential of gene expression profiling for molecular pharmacodynamics.
Main Methods:
- Nude mice bearing responsive (1A9) and non-responsive (1A9PTX22) ovarian carcinoma xenografts were treated with paclitaxel.
- Tumor tissues were analyzed using cDNA microarray 4 and 24 hours post-treatment.
- Key gene modulations were validated by Northern analyses.
Main Results:
- Paclitaxel treatment modulated gene expression differently in responsive versus non-responsive xenografts.
- Significant gene expression alterations were observed 24 hours post-treatment, affecting cell cycle, apoptosis, signal transduction, and metabolism.
- Modulation of CDKN1A and TOP2A expression correlated directly with paclitaxel responsiveness.
Conclusions:
- Gene expression profiling of xenograft models is feasible for studying drug effects in vivo.
- Observed gene expression changes provide insights into paclitaxel's mechanism of action and can predict tumor response.
- This approach can form the basis for novel molecular pharmacodynamics strategies in cancer treatment.
