Hormonal palliation of chemoresistant ovarian cancer: three consecutive phase II trials of the Mid-Atlantic Oncology Program.

Ahlgren, James D.; Ellison, Neil M.; Gottlieb, Robert J.; Laluna, F; Lokich, Jacob J.; Sinclair, Piriyah; Ueno, Winston; Wampler, Galen L.; Yeung, Katherine; Alt, D

doi:10.1200/jco.1993.11.10.1957

Cited by 97 publications

(49 citation statements)

References 64 publications

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“…The response rate in patients with chemoresistant ovarian carcinoma treated with tamoxifen (20 mg day-') is 7% (Ahlgren et al, 1993). Thus, the responses, initially to bryostatin 1 and subsequently to tamoxifen, seen in these patients, although anecdotal, were unexpected and prompted this investigation into combining these agents.…”

Section: Discussionmentioning

confidence: 99%

Bryostatin 1-tamoxifen combinations show synergistic effects on the inhibition of growth of P388 cells in vitro

McGown

Jayson²,

Pettit³

et al. 1998

Br J Cancer

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Summary This study shows that combinations of bryostatin 1, a novel modulator of protein kinase C currently under clinical evaluation, with the anti-oestrogenic agent tamoxifen caused a large synergistic enhancement of growth inhibition in P388 cells in vitro. The growth-inhibitory effects of bryostatin 1 in the presence of non-inhibitory concentrations of tamoxifen were increased by approximately 200-fold, whereas growth inhibition by tamoxifen in the presence of non-inhibitory concentrations of bryostatin 1 were increased over 30-fold. These data have been confirmed by isobologram analysis. The precise mechanism underlying this effect is unknown, although preliminary data implicating protein kinase C is presented. The magnitude of this synergistic effect, together with evidence of clinical responses seen when these agents were given sequentially in ovarian cancer, merits further study.

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Section: Discussionmentioning

confidence: 99%

Bryostatin 1-tamoxifen combinations show synergistic effects on the inhibition of growth of P388 cells in vitro

McGown

Jayson²,

Pettit³

et al. 1998

Br J Cancer

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“…Although the majority of primary ovarian tumors express ERs (26), the efficacy of endocrine therapies has not been adequately evaluated in ovarian cancer. Clinical studies of tamoxifen in a small number of chemoresistant ovarian cancer patients have demonstrated that a small subset of unselected patients responds to tamoxifen treatment (26)(27)(28). However, a recent study has demonstrated that preselection of ovarian cancer patients according to ER status results in a significantly higher percentage of patients responding to antihormonal therapy (29).…”

Section: Hoxb13 Abrogates the Antagonistic Effect Of Tamoxifenmentioning

confidence: 92%

HOXB13 promotes ovarian cancer progression

Miao

Wang

Provencher

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

106

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Deregulated expression of HOXB13 in a subset of estrogen receptor-positive breast cancer patients treated with tamoxifen monotherapy is associated with an aggressive clinical course and poor outcome. Because the ovary is another hormone-responsive organ, we investigated whether HOXB13 plays a role in ovarian cancer progression. We show that HOXB13 is expressed in multiple human ovarian cancer cell lines and tumors and that knockdown of endogenous HOXB13 by RNA interference in human ovarian cancer cell lines is associated with reduced cell proliferation. Ectopic expression of HOXB13 is capable of transforming p53 ؊/؊ mouse embryonic fibroblasts and promotes cell proliferation and anchorage-independent growth in mouse ovarian cancer cell lines that contain genetic alterations in p53, myc, and ras. In this genetically defined cell line model of ovarian cancer, we demonstrate that HOXB13 collaborates with activated ras to markedly promote tumor growth in vivo and that HOXB13 confers resistance to tamoxifen-mediated apoptosis. Taken together, our results support a pro-proliferative and pro-survival role for HOXB13 in ovarian cancer.T he HOX family of homeobox genes is an important group of developmental transcriptional regulators that are critical for various aspects of differentiation and morphogenesis (1). Similar to other genes that regulate normal growth and differentiation, HOX genes have been implicated in different aspects of the oncogenic process, because ectopic expression of HOX genes promotes cellular transformation in vitro and tumorigenesis in vivo (2). Of particular interest to human tumorigenesis is the observation that various human tumors including breast, colon, prostate, and lung carcinomas display altered HOX gene expression (3-7). Several HOX family members have been implicated in ovarian cancer differentiation (8, 9), although it is unknown whether HOX genes play a direct role in ovarian cancer progression.We recently demonstrated that dysregulated HOXB13 expression in human breast cancer is directly correlated with poor clinical outcome in estrogen receptor (ER)-positive breast cancer patients treated with tamoxifen monotherapy (10). In preliminary functional studies, we demonstrated that ectopic expression of HOXB13 in a nontransformed human mammary epithelial cell confers increased cell migration and invasion, two characteristics associated with tumor aggressiveness (10). Consistent with a possible role in human tumorigenesis, others have recently shown that HOXB13 is overexpressed in human endometrial, ovarian, and cervical carcinomas and that overexpression of HOXB13 is associated with the invasiveness of ovarian and endometrial cancer cells (11-13). Collectively, these observations suggest that HOXB13 may play an important role in tumors arising from endocrine-responsive organs. Herein, we characterized the expression of HOXB13 in ovarian cancer cell lines and tumors. Furthermore, we investigated the potential growth modulatory role of HOXB13 in vitro and in a genetically defined mouse mod...

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“…trials of palliative chemotherapy in small-cell lung cancer (James et al, 1996) and hormonal palliation of ovarian cancer (Ahlgren et al, 1993)]. In other reported trials, palliation is defined as the treatment given to prevent medical conditions arising [e.g.…”

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confidence: 99%

Defining and analysing symptom palliation in cancer clinical trials: a deceptively difficult exercise

Stephens¹,

Hopwood

Girling³

1999

Br J Cancer

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The assessment of symptom palliation is an essential component of many treatment comparisons in clinical trials, yet an extensive literature search revealed no consensus as to its precise definition, which could embrace relief of symptoms, time to their onset, duration, degree, as well as symptom control and prevention. In an attempt to assess the importance of these aspects and to compare different methods of analysis, we used one symptom (cough) from a patient self-assessment questionnaire (the Rotterdam Symptom Checklist) in a large (>300 patient) multicentre randomized clinical trial (conducted by the Medical Research Council Lung Cancer Working Party) of palliative chemotherapy in small-cell lung cancer. The regimens compared were a two-drug regimen (2D) and a four-drug regimen (4D). No differences were seen between the regimens in time of onset of palliation or its duration. The degree of palliation was strongly related to the initial severity: 90% of the patients with moderate or severe cough at baseline reported improvement, compared with only 53% of those with mild cough. Analyses using different landmark time points gave conflicting results: the 4D regimen was superior at 1 month and at 3 months, whereas at 2 months the 2D regimen appeared superior. When improvement at any time up to 3 months was considered, the 4D regimen showed a significant benefit (4D 79%, 2D 60%, P = 0.02). These findings emphasize the need for caution in interpreting results, and the importance of working towards a standard definition of symptom palliation. The current lack of specified criteria makes analysis and interpretation of trial results difficult, and comparison across trials impossible. A standard definition of palliation for use in the analysis of clinical trials data is proposed, which takes into account aspects of onset, duration and degree of palliation, and symptom improvement, control and prevention. © 1999 Cancer Research Campaign

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Hormonal palliation of chemoresistant ovarian cancer: three consecutive phase II trials of the Mid-Atlantic Oncology Program.

Abstract: Antiestrogen therapy may offer the possibility of useful and, occasionally, long-term palliation of refractory epithelial ovarian carcinoma, with little toxicity. There may be a trend toward a dose-response effect, which represents a suitable topic for a future prospective trial.

Cited by 97 publications

References 64 publications

Bryostatin 1-tamoxifen combinations show synergistic effects on the inhibition of growth of P388 cells in vitro

Bryostatin 1-tamoxifen combinations show synergistic effects on the inhibition of growth of P388 cells in vitro

HOXB13 promotes ovarian cancer progression

Defining and analysing symptom palliation in cancer clinical trials: a deceptively difficult exercise

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