Phase I study of irinotecan and gefitinib in patients with gefitinib treatment failure for non-small cell lung cancer

Horiike, Atsushi; Kudo, Kazuhiko; Miyauchi, Eisaku; Ohyanagi, Fumiyoshi; Kondo, Kazuo; Horai, Takeshi; Nishio, Makoto

doi:10.1038/bjc.2011.375

Cited by 10 publications

(5 citation statements)

References 33 publications

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“…Therefore, clinical studies of irinotecan plus other agents aimed at improving its safety and efficacy were paid much attention. It was reported that irinotecan in combination with tyrosine kinase inhibitors(TKIs) such as telatinib and sorafenib caused apparent anti-tumor activity in patients with solid tumors and such strategies was tolerated [ 34 , 35 ] which indicated that tyrosine kinase inhibitors may synergize with irinotecan to suppress HCC. Thus, to identify the candidate TKI(s) which could improve the safety and efficacy of irinotecan, we performed an in-vitro screening of a TKI library using a SRB assay.…”

Section: Discussionmentioning

confidence: 99%

Gefitinib Synergizes with Irinotecan to Suppress Hepatocellular Carcinoma via Antagonizing Rad51-Mediated DNA-Repair

Shao

Peng

et al. 2016

PLoS ONE

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Chemotherapy is the only choice for most of the advanced hepatocellular carcinoma (HCC) patients, while few agents were available, making it an urgent need to develop new chemotherapy strategies. A phase II clinical trial suggested that the efficacy of irinotecan in HCC was limited due to dose-dependent toxicities. Here, we found that gefitinib exhibited synergistic activity in combination with SN-38, an active metabolite of irinotecan, in HCC cell lines. And the enhanced apoptosis induced by gefitinib plus SN-38 was a result from caspase pathway activation. Mechanistically, gefitinib dramatically promoted the ubiquitin–proteasome-dependent degradation of Rad51 protein, suppressed the DNA repair, gave rise to more DNA damages, and ultimately resulted in the synergism of these two agents. In addition, the increased antitumor efficacy of gefitinib combined with irinotecan was further validated in a HepG2 xenograft mice model. Taken together, our data demonstrated for the first time that the combination of irinotecan and gefitinib showed potential benefit in HCC, which suggests that Rad51 is a promising target and provides a rationale for clinical trials investigating the efficacy of the combination of topoisomerase I inhibitors and gefitinib in HCC.

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Section: Discussionmentioning

confidence: 99%

Gefitinib Synergizes with Irinotecan to Suppress Hepatocellular Carcinoma via Antagonizing Rad51-Mediated DNA-Repair

Shao

Peng

et al. 2016

PLoS ONE

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“…A similar strategy was used previously for breast cancer, and is the basis for combined targeted therapy. A study by Nishio et al showed that the epidermal growth factor receptor (EGFR) inhibitor, gefitinib, suppressed serum androgen levels; moreover, gefitinib responders had significantly lower androgen levels than non-responders in female NSCLC patients ( 70 – 72 ). Kerr et al used laser capture microdissection of tumor specimens to analyze NSCLC gene expression, showing that both ERα and ERβ mRNA transcripts are expressed at higher levels in NSCLC cells compared with normal lung ( 63 ).…”

Section: Literature Analysismentioning

confidence: 99%

Sex Differences and Bone Metastases of Breast, Lung, and Prostate Cancers: Do Bone Homing Cancers Favor Feminized Bone Marrow?

et al. 2017

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Sex-associated differences in bone metastasis formation from breast, lung, and prostate cancer exist in clinical studies, but have not been systematically reviewed. Differences in the bone marrow niche can be attributed to sexual dimorphism, to genetic variations that affect sex hormone levels, or to the direct effects of sex hormones, natural or exogenously delivered. This review describes the present understanding of sex-associated and sex hormone level differences in the marrow niche and in formation of bone metastasis during the transition of these three cancers from treatable disease to an often untreatable, lethal metastatic one. Our purpose is to provide insight into some underlying molecular mechanisms for hormonal influence in bone metastasis formation, and to the potential influence of sexual dimorphism, genetic differences affecting sex assignment, and sex hormone level differences on the bone niche and its favorability for metastasis formation. We reviewed publications in PubMed and EMBASE, including full length manuscripts, case reports, and clinical studies of relevance to our topic. We focused on bone metastasis formation in breast, lung, and prostate cancer because all three commonly present with bone metastases. Several clear observations emerged. For breast cancer bone metastasis formation, estrogen receptor (ER) signaling pathways indicate a role for ER beta (ERβ). Estrogen influences the bone microenvironment, creating and conditioning a favorable niche for colonization and breast cancer progression. For lung cancer, studies support the hypothesis that females have a more favorable bone microenvironment for metastasis formation. For prostate cancer, a decrease in the relative androgen to estrogen balance or a “feminization” of bone marrow favors bone metastasis formation, with a potentially important role for ERβ that may be similar to that in breast cancer. Long-term estrogen administration or androgen blockade in males may feminize the bone marrow niche to one more favorable for bone metastases in prostate cancer. Administration of androgens in females, especially combined with mastectomy, may reduce risk of developing bone metastatic breast cancer. We conclude that it should be considered that females, those with female-leaning genetic variations, or hormonal states that feminize the bone marrow, may offer favorable sites for bone metastases.

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“…Apoptotic cell death induced by gefitinib is accompanied by G0/G1 cell cycle arrest with down-regulation of CDKs/cyclins [13] and anti-apoptotic proteins [12]. Moreover, gefitinib alone or in combination with other chemotherapy shows clinically meaningful antitumor activity in patients with advanced lung cancer [14-16]. However, the therapeutic efficacy of gefitinib increases noticeably in patients with lung cancer who have somatic mutations in the EGFR TK domain such as deletions in exon 19 or a point mutation (L858R) in exon 21 [17, 18].…”

Section: Introductionmentioning

confidence: 99%

EGFR endocytosis is a novel therapeutic target in lung cancer with wild-type EGFR

Park

Whang

et al. 2014

Oncotarget

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Oncogenic alterations of epidermal growth factor receptor (EGFR) signaling are frequently observed in lung cancer patients with worse differentiation and poor prognosis. However, the therapeutic efficacy of EGFR-tyrosine kinase inhibitors (TKIs) is currently limited in selected patients with EGFR mutations. Therefore, in this study, we investigated the potential molecular mechanism that contributes to cell viability and the response of gefitinib, one of the EGFR-TKIs, in lung cancer models with wide-type EGFR (wtEGFR). Interestingly, we found that EGF-induced EGFR endocytosis is existed differently between gefitinib-sensitive and -insensitive lung cancer cell lines. Suppressing EGFR endocytos decreased cell viability and increased apoptotic cell death in gefitinib-insensitive lung cancer with wtEGFR in vitro and in vivo. In addition, we found that Rab25 was differentially expressed in between gefitinib-sensitive and -insensitive lung cancer cells. Rab25 knockdown caused the changed EGFR endocytosis and reverted the gefitinib response in gefitinib-sensitive lung cancer with wtEGFR in vitro and in vivo. Taken together, our findings suggest a novel insight that EGFR endocytosis is a rational therapeutic target in lung cancer with wtEGFR, in which the combined efficacy with gefitinib is expected. Furthermore, we demonstrated that Rab25 plays an important role in EGFR endocytosis and gefitinib therapy.

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Phase I study of irinotecan and gefitinib in patients with gefitinib treatment failure for non-small cell lung cancer

Cited by 10 publications

References 33 publications

Gefitinib Synergizes with Irinotecan to Suppress Hepatocellular Carcinoma via Antagonizing Rad51-Mediated DNA-Repair

Gefitinib Synergizes with Irinotecan to Suppress Hepatocellular Carcinoma via Antagonizing Rad51-Mediated DNA-Repair

Sex Differences and Bone Metastases of Breast, Lung, and Prostate Cancers: Do Bone Homing Cancers Favor Feminized Bone Marrow?

EGFR endocytosis is a novel therapeutic target in lung cancer with wild-type EGFR

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