Expression, mutational analysis and in vitro response of imatinib mesylate and nilotinib target genes in ovarian granulosa cell tumors

Chu, Simon; Alexiadis, Maria; Fuller, Peter J.

doi:10.1016/j.ygyno.2007.09.017

Cited by 29 publications

(34 citation statements)

References 33 publications

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“…Other Bcr-Abl inhibitors used with increasing frequency may have narrower (nilotinib) or broader (dasatinib) target profiles, and "off-target" (e.g., non-Bcr-Abl) effects continue to be explored. The targets of imatinib-Abl, c-Kit, PDGFR-␣, and PDGFR-␤-were found to be expressed at relatively uniform levels in 10 normal human premenopausal ovaries and at variable levels in granulosa tumor-derived cell lines [25]. That publication further characterized the effect of imatinib on granulosa tumor cell line proliferation, showing dose-dependent decreases in cell proliferation and viability and increased apoptosis, with an EC50 (half maximal effective concentration) that implicated off-target effects of imatinib on granulosa cells.…”

Section: Discussionmentioning

confidence: 99%

Will Imatinib Compromise Reproductive Capacity?

et al. 2011

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Imatinib mesylate is the first in a family of highly effective, minimally toxic, targeted agents used widely to treat Philadelphia-positive leukemias and selected other cancers, leading to a steady rise in the prevalence of patients using such therapy. Because failure of therapy would require conventional gonadotoxic chemotherapeutics, many female patients using imatinib may choose to preserve fertility. Herein, we provide evidence of a potential negative effect of imatinib on ovarian function by reporting the first case of a woman who showed a severely compromised ovarian response to gonadotropin stimulation while on imatinib, with a normal ovarian response after stopping this medication.

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Section: Discussionmentioning

confidence: 99%

Will Imatinib Compromise Reproductive Capacity?

et al. 2011

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“…Several studies have shown a high expression of PDGF RTK-α as well as an increased PDGFR activity caused by autocrine or paracrine receptor activation in ovarian cancer tissue [14,15,16]. In both normal stroma and benign tumors, a significantly lower expression for PDGFR-α was observed.…”

Section: Discussionmentioning

confidence: 99%

“…RTK overexpression and increased levels of activation present key events in the neoplastic transformation and progression of different solid cancer types. Several groups reported highly expressed tyrosine kinases and their specific ligands in ovarian cancer cells and cell lines compared to normal ovarian epithelium [14,15,16,17]. Thereby, especially an autocrine PDGF-mediated activation of PDGFR-α as well as the downstream PI3K/Akt cascade seem to play an important role in the pathogenesis and progression of ovarian cancer [15,18].…”

Section: Introductionmentioning

confidence: 99%

Nilotinib in Combination with Carboplatin and Paclitaxel Is a Candidate for Ovarian Cancer Treatment

Weigel

Rath²,

Alkatout³

et al. 2014

Oncology

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Purpose: Nilotinib is a selective tyrosine kinase inhibitor of c-Kit, Abl and platelet-derived growth factor receptor-α/β. To evaluate nilotinib's potential use as a treatment of human ovarian cancer, we tested nilotinib's preclinical activity in ovarian cancer cell lines with different tyrosine kinase expression patterns. Methods: The effects of nilotinib on ovarian cancer cell growth were studied alone and in combination with carboplatin and paclitaxel. Proapoptotic and antimigratory effects were examined using TUNEL and migration assays. Results: Nilotinib alone and in combination with carboplatin and paclitaxel significantly inhibited cell growth in PDGFR-α-positive ovarian cancer cell lines. The combination of nilotinib with carboplatin and paclitaxel showed synergistic effects on cell proliferation. Nilotinib treatment led to the inhibition of cell migration alone and in combination with carboplatin and paclitaxel. Apoptosis induction occurred in response to nilotinib that increased in combination with carboplatin. Conclusions: Nilotinib may be a feasible targeted therapy option for the treatment of ovarian cancer.

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“…5,[14][15][16][17][18][19] Normal ovarian tissue was obtained from premenopausal women who had undergone elective hysterectomy with oophorectomy for a range of conditions not associated with ovarian malignancy (Supplementary Table 1). RNA from the tissue and the two granulosa cell tumorderived cell lines was extracted using the guanidine thiocyanate/cesium chloride method as described previously.…”

Section: Melbournementioning

confidence: 99%

The FOXL2 C134W mutation is characteristic of adult granulosa cell tumors of the ovary

et al. 2010

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Granulosa cell tumors of the ovary represent B5% of malignant ovarian cancers. It has recently been reported that 95-97% of adult granulosa cell tumors carry a unique somatic mutation in the FOXL2 gene. We undertook this study to verify the presence of the FOXL2 Cys134Trp mutation in two geographically independent cohorts of granulosa cell tumors and to examine the expression pattern of FOXL2 in these tumors. A total of 56 tumors with the histological diagnosis of adult granulosa cell tumor from two centers, Melbourne and Helsinki, were examined for the presence of the mutation using direct sequence analysis. Two granulosa cell tumor-derived cell lines, COV434 and KGN, three juvenile granulosa cell tumors and control tissues were also examined. The expression of the FOXL2 gene was determined using quantitative RT-PCR and/or immunohistochemistry. We found that 52 of the 56 adult granulosa cell tumors harbor the mutation, of which three were hemi/homozygous. Of the four cases with wild-type FOXL2 sequence, reappraisal suggests that three may have been misclassified at primary diagnosis. The KGN cells were heterozygous for the mutation, whereas the COV434 cells had a wildtype FOXL2 genotype. The expression levels of FOXL2 were similar across the adult granulosa cell tumors and the normal ovary controls; one mutation-negative granulosa cell tumor had high FOXL2 mRNA levels, whereas the COV434 cells and two of the three juvenile granulosa cell tumors lacked the expression of FOXL2. Our data provide confirmation of the frequent presence of the FOXL2 C134W mutation in adult granulosa cell tumors and demonstrate that the mutation is not associated with altered FOXL2 expression. The mutation analysis may be a useful tool to differentiate particularly between cell-rich diffuse granulosa cell tumors and mitotically active sex cord-stromal tumors. This unique FOXL2 mutation appears to be characteristic of adult granulosa cell tumors.

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Expression, mutational analysis and in vitro response of imatinib mesylate and nilotinib target genes in ovarian granulosa cell tumors

Cited by 29 publications

References 33 publications

Will Imatinib Compromise Reproductive Capacity?

Will Imatinib Compromise Reproductive Capacity?

Nilotinib in Combination with Carboplatin and Paclitaxel Is a Candidate for Ovarian Cancer Treatment

The FOXL2 C134W mutation is characteristic of adult granulosa cell tumors of the ovary

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