Proliferative subtype

Paclitaxel (Taxol)

http://en.wikipedia.org/wiki/Mitotic_inhibitor
http://mct.aacrjournals.org/content/3/2/111.full


http://www.nature.com/nrd/journal/v9/n10/full/nrd3253.html?hilite_compound=false

Microtubule-binding agents: a dynamic field of cancer therapeutics

Charles Dumontet & Mary Ann Jordan

Abstract

Microtubules are dynamic filamentous cytoskeletal proteins composed of tubulin and are an important therapeutic target in tumour cells. Agents that bind to microtubules have been part of the pharmacopoeia of anticancer therapy for decades and until the advent of targeted therapy, microtubules were the only alternative to DNA as a therapeutic target in cancer. The screening of a range of botanical species and marine organisms has yielded promising new antitubulin agents with novel properties. In the current search for novel microtubule-binding agents, enhanced tumour specificity, reduced neurotoxicity and insensitivity to chemoresistance mechanisms are the three main objectives.

Clin Breast Cancer. 2004 Feb;4(6):415-9.

Paclitaxel improves the prognosis in estrogen receptor negative inflammatory breast cancer: the M. D. Anderson Cancer Center experience.

Cristofanilli M, Gonzalez-Angulo AM, Buzdar AU, Kau SW, Frye DK, Hortobagyi GN.

Source

Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, 77030, USA. mcristof@mdanderson.org

Abstract

The treatment of inflammatory breast cancer includes preoperative anthracycline-based chemotherapy, surgery, and radiation therapy. In the past few years, taxanes, mainly paclitaxel, have been frequently used for preoperative chemotherapy, usually in sequence with anthracyclines. The purpose of this retrospective analysis was to determine how adding paclitaxel to anthracycline-based regimens affects prognosis. A total of 240 patients treated in 6 consecutive trials between 1973 and 2000 were included in the analysis. Group 1 (N = 178) consisted of patients treated in the first 4 trials (1973-1993) with FAC (5-fluorouracil/doxorubicin/cyclophosphamide) based regimens. Group 2 (N = 62) consisted of patients treated in the last 2 trials (1994-2000) with FAC followed by paclitaxel given every 3 weeks or given in a high-dose weekly schedule. The 2 groups differed with respect to median follow-up durations, which were 148 months (range, 85-283 months) in group 1 and 45 months (range, 21-99 months) in group 2. Estrogen receptor (ER) status was negative in 58 cases (33%) in group 1 and 40 cases (65%) in group 2. There was no difference in median age between the groups. The objective response rates (complete and partial) were similar (group 1, 74%; group 2, 82%). The median overall survival (OS) and progression-free survival (PFS) were better in the patients treated with paclitaxel, and these differences reached statistical significance in the patients with ER-negative disease (median OS: group 1, 32 months; group 2, 54 months; P = 0.03; median PFS: group 1, 18 months; group 2, 27 months; P = 0.04). It may be concluded that the addition of paclitaxel to anthracycline-based therapy resulted in a statistically significant improvement in outcome in patients with ER-negative inflammatory breast cancer.

Paclitaxel (Taxol) upregulates expression of functional interleukin-6 in human ovarian cancer cells through multiple signaling pathways

Oncogene (2006) 25, 4857–4866. doi:10.1038/sj.onc.1209498; published online 20 March 2006

Paclitaxel (Taxol) is an antineoplastic agent that specifically targets microtubules and arrests cells at the G2/M phase of the cell cycle. In addition to mitotic arrest, the activation of c-Jun N-terminal kinase (JNK) signaling pathway has been demonstrated to be involved in the process leading to apoptosis. In an attempt to explore what genes are transcriptionally regulated by the activated JNK signaling pathway upon paclitaxel treatment, we used cDNA microarrays to analyse the changes of gene expression in human ovarian cancer cells that were treated with paclitaxel and/or the JNK inhibitor SP600125. Among 20 genes that were specifically regulated by the paclitaxel-activated JNK pathway, interleukin (IL)-6 was shown to elicit function through the JAK–STAT signaling pathway in an autocrine and/or paracrine fashion. Subsequently, we identified that 87.5% of eight tested ovarian cancer lines secreted detectable levels of IL-6, which could be further upregulated 2–3.2 fold by 1 m paclitaxel. Dissection on regulatory pathways for IL-6 indicated that (i) when ovarian cancer cells were treated with paclitaxel at low but clinically achievable concentrations (exemplified by 1 m in this study), the JNK signaling pathway was the major stimulator of IL-6 gene regulation and (ii) at suprapharmacologically high concentrations (exemplified by 50 m), paclitaxel exerted lipopolysaccharide-like effects, most likely through the Toll-like receptor 4 signaling pathway. Collectively, these results suggest that paclitaxel upregulates functional IL-6 expression in human ovarian cancer cells through multiple signaling pathways.




http://www.clearityfoundation.org/taxanes-references.aspx

Taxane sensitivity: BRCA1

Quinn, J. E., C. R. James, et al. (2007). "BRCA1 mRNA expression levels predict for overall survival in ovarian cancer after chemotherapy." Clin Cancer Res 13(24): 7413-7420.

Boukovinas, I., C. Papadaki, et al. (2008). "Tumor BRCA1, RRM1 and RRM2 mRNA expression levels and clinical response to first-line gemcitabine plus docetaxel in non-small-cell lung cancer patients." PLoS One 3(11): e3695.

Su, C., S. Zhou, et al. (2010). "ERCC1, RRM1 and BRCA1 mRNA expression levels and clinical outcome of advanced non-small cell lung cancer." Med Oncol.

Papadaki, C., E. Tsaroucha, et al. (2011). "Correlation of BRCA1, TXR1 and TSP1 mRNA expression with treatment outcome to docetaxel-based first-line chemotherapy in patients with advanced/metastatic non-small-cell lung cancer." Br J Cancer104(2): 316-323.

Nab-paclitaxel sensitivity: SPARC

Desai, N., V. Trieu, et al. (2009). "SPARC Expression Correlates with Tumor Response to Albumin-Bound Paclitaxel in Head and Neck Cancer Patients." Transl Oncol 2(2): 59-64.

Taxane resistance: TUBB3

Mozzetti, S., C. Ferlini, et al. (2005). "Class III beta-tubulin overexpression is a prominent mechanism of paclitaxel resistance in ovarian cancer patients." Clin Cancer Res 11(1): 298-305.

Ohishi, Y., Y. Oda, et al. (2007). "Expression of beta-tubulin isotypes in human primary ovarian carcinoma." Gynecol Oncol105(3): 586-592.

Umezu, T., K. Shibata, et al. (2008). "Taxol resistance among the different histological subtypes of ovarian cancer may be associated with the expression of class III beta-tubulin." Int J Gynecol Pathol 27(2): 207-212.

Ferrandina, G., G. F. Zannoni, et al. (2006). "Class III beta-tubulin overexpression is a marker of poor clinical outcome in advanced ovarian cancer patients." Clin Cancer Res 12(9): 2774-2779.

Taxane resistance: PGP

Kamazawa, S., J. Kigawa, et al. (2002). "Multidrug resistance gene-1 is a useful predictor of Paclitaxel-based chemotherapy for patients with ovarian cancer." Gynecol Oncol 86(2): 171-176.

Goto, T., M. Takano, et al. (2006). "Gene expression profiles with cDNA microarray reveal RhoGDI as a predictive marker for paclitaxel resistance in ovarian cancers." Oncol Rep 15(5): 1265-1271.

Naniwa, J., J. Kigawa, et al. (2007). "Genetic diagnosis for chemosensitivity with drug-resistance genes in epithelial ovarian cancer." Int J Gynecol Cancer 17(1): 76-82.

Penson, R. T., E. Oliva, et al. (2004). "Expression of multidrug resistance-1 protein inversely correlates with paclitaxel response and survival in ovarian cancer patients: a study in serial samples." Gynecol Oncol 93(1): 98-106.

Yakirevich, E., E. Sabo, et al. (2006). "Multidrug resistance-related phenotype and apoptosis-related protein expression in ovarian serous carcinomas." Gynecol Oncol 100(1): 152-159.

Taxane resistance: ESR1

Formenti, S. C., D. Spicer, et al. (2002). "Low HER2/neu gene expression is associated with pathological response to concurrent paclitaxel and radiation therapy in locally advanced breast cancer." Int J Radiat Oncol Biol Phys 52(2): 397-405.

Ogston, K. N., I. D. Miller, et al. (2004). "Can patients' likelihood of benefiting from primary chemotherapy for breast cancer be predicted before commencement of treatment?" Breast Cancer Res Treat 86(2): 181-189.

Kim, S. J., Y. Miyoshi, et al. (2005). "High thioredoxin expression is associated with resistance to docetaxel in primary breast cancer." Clin Cancer Res 11(23): 8425-8430.

Lee, K. H., S. A. Im, et al. (2007). "Prognostic significance of bcl-2 expression in stage III breast cancer patients who had received doxorubicin and cyclophosphamide followed by paclitaxel as adjuvant chemotherapy." BMC Cancer 7: 63.

Warm, M., R. Kates, et al. (2007). "Impact of tumor biological factors on response to pre-operative epirubicin and paclitaxel chemotherapy in primary breast cancer." Anticancer Res 27(2): 1031-1038.

Zhou, B., D. Q. Yang, et al. (2008). "Biological markers as predictive factors of response to neoadjuvant taxanes and anthracycline chemotherapy in breast carcinoma." Chin Med J (Engl) 121(5): 387-391.

Jeong, J. H., S. Y. Jung, et al. (2010). "Predictive factors of pathologic complete response and clinical tumor progression after preoperative chemotherapy in patients with stage II and III breast cancer." Invest New Drugs.

Taxane resistance: Survivin

Duan, Z., E. J. Weinstein, et al. (2008). "Lentiviral short hairpin RNA screen of genes associated with multidrug resistance identifies PRP-4 as a new regulator of chemoresistance in human ovarian cancer." Mol Cancer Ther 7(8): 2377-2385.

Zaffaroni, N., M. Pennati, et al. (2002). "Expression of the anti-apoptotic gene survivin correlates with taxol resistance in human ovarian cancer." Cell Mol Life Sci 59(8): 1406-1412.