Laboratory and Clinical Evidence of Synergistic Cytotoxicity of Sequential Treament With Gemcitabine Followed by Docetaxel in the Treatment of Sarcoma

Leu, Kirsten; Ostruszka, Leo J.; Shewach, Donna S.; Zalupski, Mark M.; Sondak, Vernon K.; Biermann, J. Sybil; Lee, Julia Shin-Jung; Couwlier, C; Palazzolo, Krisinda; Baker, Laurence H.

doi:10.1200/jco.2004.08.043

Cited by 223 publications

(179 citation statements)

References 28 publications

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“…Our results contrast with those of the combination of gemcitabine and docetaxel (TXT), an agent with limited activity in ASTS (van Hoesel et al, 1994;Verweij et al, 2000). This combination induced a 43 -53% remission rate in two Phase II studies, an efficacy that was almost limited to patients with leiomyosarcoma of any origin (Hensley et al, 2002;Leu et al, 2004). In our series, 50% of leiomyosarcoma patients responded to therapy, which confirms the sensitivity of this histotype to gemcitabine-containing combinations .…”

Section: Discussioncontrasting

confidence: 40%

“…In our series, 50% of leiomyosarcoma patients responded to therapy, which confirms the sensitivity of this histotype to gemcitabine-containing combinations . In those studies, only gemcitabine was given on day 1, whereas on day 8 gemcitabine preceded TXT, a sequence that was synergistic in an osteosarcoma and a breast cancer cell line (Leu et al, 2004); however, in lung cancer cell lines, the opposite sequence was more effective (Zoli et al, 1999). Similarly, in vitro studies have shown that the effects of a combination of DXR and gemcitabine depend both on the sequence of administration and on the particular cell line studied (Chow et al, 2000;Zoli et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

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Phase I/II trial of doxorubicin and fixed dose-rate infusion gemcitabine in advanced soft tissue sarcomas: a GEIS study

et al. 2006

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The aim of the study was to determine the dose-limiting toxicity and maximum tolerated dose of a first-line combination of doxorubicin and gemcitabine in adult patients with advanced soft tissue sarcomas and to explore its activity and toxicity, and the presence of possible interactions between these agents. Patients with measurable disease were initially treated with doxorubicin 60 mg m À2 by i.v. bolus on day 1 followed by gemcitabine at 800 mg m À2 over 80 min on days 1 and 8, every 21 days. Concentrations of gemcitabine and 2 0 ,2 0 -difluorodeoxyuridine in plasma, and gemcitabine triphosphate levels in peripheral blood mononuclear cells were determined during 8 h after the start of gemcitabine infusion. Myelosuppression and stomatitis were limiting toxicities, and the initial dose level was applied for the Phase II trial, where grade 3 -4 granulocytopenia occurred in 70% of patients, grade 3 stomatitis in 46% and febrile neutropenia in 20%. Objective activity in 36 patients was 22% (95% CI: 9 -35%), and a 50% remission rate was noted in leiomyosarcomas. Administration of doxorubicin preceding gemcitabine significantly reduced the synthesis of gemcitabine triphosphate. Clinical activity, similar to that of single-agent doxorubicin, and the toxicity encountered do not justify further studies with this schedule of administration.

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Section: Discussioncontrasting

confidence: 40%

Section: Discussionmentioning

confidence: 99%

Phase I/II trial of doxorubicin and fixed dose-rate infusion gemcitabine in advanced soft tissue sarcomas: a GEIS study

et al. 2006

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“…However, different data were observed comparing D3 G with G3 D (24-hour exposure each) in the MCF-7 breast carcinoma cell line versus the SaOS-2 osteogenic sarcoma cell line [35]. Whereas simultaneous exposure to both drugs was additive in SaOS-2 cells, the combination was antagonistic in the MCF-7 cell line.…”

Section: Gemcitabine and Docetaxel: Possible Synergy?mentioning

confidence: 79%

Gemcitabine and Docetaxel in Metastatic Sarcoma: Past, Present, and Future

Maki

2007

The Oncologist

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Objective. In the era of oral molecular kinase inhibitors, cytotoxic chemotherapy agents are somewhat overlooked, but remain the backbone of treatment for most cancers. Patients with non-gastrointestinal stromal tumor sarcomas, such as leiomyosarcoma, liposarcoma, and undifferentiated high-grade pleomorphic sarcoma (formerly called malignant fibrous histiocytoma), have received doxorubicin and ifosfamide as the backbone of their treatment for over 15 years or more. The goal of this article is to review the data that have led to the use of gemcitabine and docetaxel as a useful combination for patients with metastatic sarcomas, and to comment on possible synergy of the combination.Methods and results. The literature regarding the use of gemcitabine, docetaxel, or both, is reviewed, with emphasis on patients with metastatic sarcoma.Results. Activity of gemcitabine and docetaxel is observed in leiomyosarcoma and undifferentiated highgrade pleomorphic sarcoma. There is apparent schedule dependence of the combination in other cancers; it is unclear if schedule matters in patients with sarcomas. The dose and schedule of gemcitabine and docetaxel examined in phase II studies are probably too high for routine practice.Conclusions. The combination of gemcitabine and docetaxel is an effective option for patients with metastatic sarcoma, increasing the armamentarium for the practicing oncologist in treating this heterogeneous group of diseases. Given the low response rate to docetaxel as a single agent, it is likely that there is true clinical synergy of the combination. The Oncologist 2007;12: 999 -1006 Disclosure of potential conflicts of interest is found at the end of this article.

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“…Synergistic interactions of anticancer drugs have been reported in studies of tumor cell lines (2 -4), animal models (5), and cancer patients (6). Such interactions include, but are not limited to, the combination of discodermolide and paclitaxel (2), capsicum and green tea concentrate (4), gemcitabine and docetaxel (6), docosahexaenoic acid (DHA) and paclitaxel (7,8), and irinotecan and 5-fluorouracil (5).…”

Section: Introductionmentioning

confidence: 99%

Clioquinol and docosahexaenoic acid act synergistically to kill tumor cells

Ding

Liu

Vaught

et al. 2006

Molecular Cancer Therapeutics

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Clioquinol, an 8-hydroxyquinoline derivative (5-chloro-7-iodo-8-hydroxyquinoline) with antimicrobial properties, has recently been found to have cytotoxic activity towards human cancer cell lines at concentrations achieved by oral administration. This study was initiated to determine whether clioquinol could potentiate the antitumor effects of two drugs, doxorubicin and docosahexaenoic acid (DHA), believed to act in part via the generation of reactant oxidant species. At low micromolar concentrations, clioquinol had little effect upon cell viability and did not potentiate doxorubicin's cytotoxicity. Clioquinol significantly enhanced DHA's cytotoxic effects, an interaction that was shown to be synergistic by isobolographic analysis. Clioquinol exhibited a synergistic interaction with DHA in reducing nuclear factor-KB activity and inducing apoptosis, and the combination reduced the level of several molecules that promote cell survival, including Akt, p65, and Bcl-2. Interestingly, clioquinol neither induced lipid peroxidation itself nor increased peroxidation brought about by the addition of DHA. However, when cells were pretreated with antioxidant vitamin E, the synergism of clioquinol and DHA was blocked, indicating the essential role of lipid peroxidation for their action. These findings reveal a novel antitumor drug combination that synergistically targets major cell survival signaling pathways.

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Laboratory and Clinical Evidence of Synergistic Cytotoxicity of Sequential Treament With Gemcitabine Followed by Docetaxel in the Treatment of Sarcoma

Abstract: The combination of gemcitabine and docetaxel seems to be active in a variety of sarcomas. A multicenter, randomized clinical trial in soft tissue sarcoma comparing gemcitabine alone with this combination, is ongoing.

Cited by 223 publications

References 28 publications

Phase I/II trial of doxorubicin and fixed dose-rate infusion gemcitabine in advanced soft tissue sarcomas: a GEIS study

Phase I/II trial of doxorubicin and fixed dose-rate infusion gemcitabine in advanced soft tissue sarcomas: a GEIS study

Gemcitabine and Docetaxel in Metastatic Sarcoma: Past, Present, and Future

Clioquinol and docosahexaenoic acid act synergistically to kill tumor cells

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