Effects of bevacizumab and pegylated liposomal doxorubicin for the patients with recurrent or refractory ovarian cancers

Kudoh, Kazuya; Takano, Masashi; Kouta, Hiroko; Kikuchi, Ryoko; Kita, Toru; Miyamoto, Morikazu; Watanabe, Akio; Kato, Masafumi; Gotō, Tomoko; Kikuchi, Yoshihiro

doi:10.1016/j.ygyno.2011.04.046

Cited by 51 publications

(22 citation statements)

References 21 publications

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“…Such dual inhibition would facilitate maintaining the benefits of attenuating angiogenesis while avoiding the negative consequences of increased hypoxia, including an induced aggressive change in tumor biology (19); decreasing HIFs may also resensitize cancer cells to doxorubicin (20,21). Importantly, mTOR inhibitors interfere with signaling via the PI3K/AKT/mTOR axis, a pathway critical in many types of cancers.…”

Section: Introductionmentioning

confidence: 99%

Phase I Study of the Antiangiogenic Antibody Bevacizumab and the mTOR/Hypoxia-Inducible Factor Inhibitor Temsirolimus Combined with Liposomal Doxorubicin: Tolerance and Biological Activity

Moroney

Moulder

et al. 2012

Clinical Cancer Research

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Purpose: Preclinical data suggest that combining the mTOR/hypoxia-inducible factor (HIF) inhibitor temsirolimus and the antiangiogenesis antibody bevacizumab may augment antitumor activity as well as resensitize cells to anthracyclines.Experimental Design: We initiated a phase I study of bevacizumab and temsirolimus plus liposomal doxorubicin in patients with advanced malignancies. Patients (N ¼ 136) were enrolled according to a modified 3 þ 3 design plus dose expansion in responsive tumor types.Results: The most common cancers were breast (n ¼ 29), epithelial ovarian (n ¼ 23), and colorectal cancer (n ¼ 17). The median number of prior chemotherapy regimens was four (range: 0-16). Grade 3 or higher adverse events (> 5%) included pancytopenia, mucositis, hand-foot syndrome, hypertension, and fistula. This regimen led to a 21% (n ¼ 28) stable disease (SD) ! 6 months and 21% (n ¼ 29) rate of partial or complete remission [PR/CR; (total SD ! 6 months/PR/CR ¼ 42% (n ¼ 57)]. PR/CR was most common in parotid gland adenocarcinoma (4/6, 67%), metaplastic breast cancer (5/12, 42%), endometrial endometrioid carcinoma (6/15, 40%), and in patients with a PIK3CA mutation and/or a PTEN mutation/loss (11/28, 39%). The maximum tolerated dose was liposomal doxorubicin 30 mg/m 2 and bevacizumab 15 mg/kg every three weeks with temsirolimus 25 mg weekly. Conclusions: Patients tolerated bevacizumab and temsirolimus together with liposomal doxorubicin. Further evaluation, especially in patients with parotid, metaplastic breast, and endometrial endometrioid cancer, and in patients with PIK3CA and/or PTEN aberrations is warranted.

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Section: Introductionmentioning

confidence: 99%

Phase I Study of the Antiangiogenic Antibody Bevacizumab and the mTOR/Hypoxia-Inducible Factor Inhibitor Temsirolimus Combined with Liposomal Doxorubicin: Tolerance and Biological Activity

Moroney

Moulder

et al. 2012

Clinical Cancer Research

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“…49 In a phase II study, where bevacizumab was combined with liposomal DOX for patients with platinum and taxane resistant ovarian cancers, researchers found an increased patient response but also increased toxicity, mainly because of the nonspecificity of bevacizumab due to systemic delivery. 50 However, in the treatment of locally recurrent or MBCs, the combination of systemic bevacizumab and liposomal DOX only achieved moderate activity while higher than anticipated toxicity.…”

mentioning

confidence: 99%

Targeted multidrug delivery system to overcome chemoresistance in breast cancer

Tang

Soroush

Tong

et al. 2017

IJN

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Chemotherapy has been widely used in breast cancer patients to reduce tumor size. However, most anticancer agents cannot differentiate between cancerous and normal cells, resulting in severe systemic toxicity. In addition, acquired drug resistance during the chemotherapy treatment further decreases treatment efficacy. With the proper treatment strategy, nanodrug carriers, such as liposomes/immunoliposomes, may be able to reduce undesired side effects of chemotherapy, to overcome the acquired multidrug resistance, and to further improve the treatment efficacy. In this study, a novel combinational targeted drug delivery system was developed by encapsulating antiangiogenesis drug bevacizumab into liposomes and encapsulating chemotherapy drug doxorubicin (DOX) into immunoliposomes where the human epidermal growth factor receptor 2 (HER2) antibody was used as a targeting ligand. This novel combinational system was tested in vitro using a HER2 positive and multidrug resistant breast cancer cell line (BT-474/MDR), and in vivo using a xenograft mouse tumor model. In vitro cell culture experiments show that immunoliposome delivery led to a high cell nucleus accumulation of DOX, whereas free DOX was observed mostly near the cell membrane and in cytoplasm due to the action of P-gp. Combining liposomal bevacizumab with immunoliposomal DOX achieved the best tumor growth inhibition and the lowest toxicity. Tumor size decreased steadily within a 60-day observation period indicating a potential synergistic effect between DOX and bevacizumab through the targeted delivery. Our findings clearly indicate that tumor growth was significantly delayed in the combinational liposomal drug delivery group. This novel combinational therapy has great potential for the treatment of patients with HER2/MDR double positive breast cancer.

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“…Doxil used in combination with bevacizumab in patients with recurrent ovarian cancer achieved a 33% response rate [162]. In prostate cancer Dox has been combined with si I de na fil , which promoted apoptosis through enhancement of the intrinsic pathway including down regulation of anti-apoptotic proteins Bel-xL and reduced phosphorylation of proapoptotic protein BAD as well as induction of pro-a pop to tic protein Bax [163].…”

Section: Discussionmentioning

confidence: 99%

“…In a phase I clinical trial of 30 patients, Doxil was combined with bevacizumab in patients with recurrent or refractory ovarian cancer. Patients achieved an overall response rate of 33% and a 6-months progression free survival of 47% with no treatment related deaths [162]. Additionally, in a multicenter phase III clinical trial of 976 patients with recurrent ovarian cancer, combination of Doxil with carboplatin vs. paclitaxel with carboplatin was statistically superior resulting in reduced severe nonhematologic toxicity, 28.4%…”

Section: Doxorubicin (Dox) Is a Broad-spectrum Anthracylin Isolated Fmentioning

confidence: 96%

“…Moreover, patients treated with Doxil have a reduction in death compared to patients on topotecan [159] or paclitaxel [161]. As such it remains a standard treatment option in patients that have platinumresistant and recurrent ovarian cancer [162]. In a phase I clinical trial of 30 patients, Doxil was combined with bevacizumab in patients with recurrent or refractory ovarian cancer.…”

Section: Doxorubicin (Dox) Is a Broad-spectrum Anthracylin Isolated Fmentioning

confidence: 99%

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Development of pituitary tumor-transforming gene (PTTG) transgenic mice for the treatment of ovarian cancer.

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Effects of bevacizumab and pegylated liposomal doxorubicin for the patients with recurrent or refractory ovarian cancers

Cited by 51 publications

References 21 publications

Phase I Study of the Antiangiogenic Antibody Bevacizumab and the mTOR/Hypoxia-Inducible Factor Inhibitor Temsirolimus Combined with Liposomal Doxorubicin: Tolerance and Biological Activity

Phase I Study of the Antiangiogenic Antibody Bevacizumab and the mTOR/Hypoxia-Inducible Factor Inhibitor Temsirolimus Combined with Liposomal Doxorubicin: Tolerance and Biological Activity

Targeted multidrug delivery system to overcome chemoresistance in breast cancer

Development of pituitary tumor-transforming gene (PTTG) transgenic mice for the treatment of ovarian cancer.

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