Concurrent use of vinorelbine and gefitinib induces supra-additive effect in head and neck squamous cell carcinoma cell lines

Erjala, Kaisa; Raitanen, Mika; Kulmala, Jarmo; Grénman, Reidar

doi:10.1007/s00432-006-0154-0

Cited by 13 publications

(15 citation statements)

References 36 publications

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“…31 Early studies on HNSCC cell lines used much higher doses than this 32 while more recent studies all have used doses below 2 μM gefitinib. 33,34 The relative insensitivity of the cell line to gefitinib in combination with the development of their relative efficiencies in the nucleus are unknown. siRNAs exert their effect mainly in the cytoplasm of cells, 37 but if efficient will reduce nuclear as well as membranous and cytoplasmic receptor levels.…”

Section: Discussionmentioning

confidence: 99%

Studies on the inhibition of feline EGFR in squamous cell carcinoma: Enhancement of radiosensitivity and rescue of resistance to small molecule inhibitors

Bergkvist¹,

Argyle²,

Pang³

et al. 2011

Cancer Biology & Therapy

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Section: Discussionmentioning

confidence: 99%

Studies on the inhibition of feline EGFR in squamous cell carcinoma: Enhancement of radiosensitivity and rescue of resistance to small molecule inhibitors

Bergkvist¹,

Argyle²,

Pang³

et al. 2011

Cancer Biology & Therapy

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“…Gefitinib and vinorelbine combinations have been investigated previously in preclinical studies using tumor cell line models of head and neck squamous cell carcinoma (HNSCC) and NSCLC. 58,59 In a panel of six HNSCC tumor cell lines, the combination of gefitinib plus vinorelbine had a supra-additive cytotoxic effect in four of six cell lines, and additive cytotoxic effects in the other two cell lines. 58 Gefitinib and vinorelbine are both metabolized by the CYP3A4 P450 isoenzyme, and when co-administered in vivo, drug-drug interactions may alter their respective exposure levels.…”

Section: Discussionmentioning

confidence: 99%

“…58,59 In a panel of six HNSCC tumor cell lines, the combination of gefitinib plus vinorelbine had a supra-additive cytotoxic effect in four of six cell lines, and additive cytotoxic effects in the other two cell lines. 58 Gefitinib and vinorelbine are both metabolized by the CYP3A4 P450 isoenzyme, and when co-administered in vivo, drug-drug interactions may alter their respective exposure levels. 58 In 17 NSCLC cell lines that included 4 that overexpressed P-glycoprotein (Pgp/MDR1) and 3 with sensitizing EGF-R mutations, combinations of gefitinib with vinorelbine exhibited synergism (mean CIs <1) in cell lines without sensitizing EGF-R mutations.…”

Section: Discussionmentioning

confidence: 99%

Implementation of the NCI-60 Human Tumor Cell Line Panel to Screen 2260 Cancer Drug Combinations to Generate >3 Million Data Points Used to Populate a Large Matrix of Anti-Neoplastic Agent Combinations (ALMANAC) Database

Wang

Kochanek

et al. 2019

SLAS Discovery

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Animal and clinical studies demonstrate that cancer drug combinations (DCs) are more effective than single agents. However, it is difficult to predict which DCs will be more efficacious than individual drugs. Systematic DC high-throughput screening (HTS) of 100 approved drugs in the National Cancer Institute's panel of 60 cancer cell lines (NCI-60) produced data to help select DCs for further consideration. We miniaturized growth inhibition assays into 384-well format, increased the fetal bovine serum amount to 10%, lengthened compound exposure to 72 h, and used a homogeneous detection reagent. We determined the growth inhibition 50% values of individual drugs across 60 cell lines, selected drug concentrations for 4 × 4 DC matrices (DCMs), created DCM master and replica daughter plate sets, implemented the HTS, quality control reviewed the data, and analyzed the results. A total of 2620 DCMs were screened in 60 cancer cell lines to generate 3.04 million data points for the NCI ALMANAC (A Large Matrix of Anti-Neoplastic Agent Combinations) database. We confirmed in vitro a synergistic drug interaction flagged in the DC HTS between the vinca-alkaloid microtubule assembly inhibitor vinorelbine (Navelbine) tartrate and the epidermal growth factor-receptor tyrosine kinase inhibitor gefitinib (Iressa) in the SK-MEL-5 melanoma cell line. Seventy-five percent of the DCs examined in the screen are not currently in the clinical trials database. Selected synergistic drug interactions flagged in the DC HTS described herein were subsequently confirmed by the NCI in vitro, evaluated mechanistically, and were shown to have greater than single-agent efficacy in mouse xenograft human cancer models. Enrollment is open for two clinical trials for DCs that were identified in the DC HTS. The NCI ALMANAC database therefore constitutes a valuable resource for selecting promising DCs for confirmation, mechanistic studies, and clinical translation.

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“…[14][15][16][17][18][27][28][29] Only limited data are currently available on the efficacy of combining VNB with GEF on NSCLC to treat in vitro and in vivo models. Erjala et al 26 have shown that the concomitant use of VNB and GEF induced both an additive and a supra-additive cytotoxic effect in six different head and neck SCC cell lines, whereas studies in vivo have shown that the combination of GEF with VNB was active but not well tolerated. 37,38 Tsai et al demonstrated synergism in combining GEF with antimicrotubule agents using a panel of 12 NSCLC cell lines that had no sensitizing EGFR mutations (SEM).…”

Section: Discussionmentioning

confidence: 99%

“…Erjala et al have evaluated the efficacy of the concomitant treatment of VNB and GEF in cell lines of primary squamous cell carcinoma (SCC) of the head and neck, and a clear additive or supra-additive effect was demonstrated. 26 Moreover, in vitro experiments have shown that the antitumor effects that are produced by administering GEF in combination with chemotherapy are both enhanced and dependent on the sequence of treatment. 27,28 On the contrary, controversial data on disease-free survival rates were found when using the sequential treatment of GEF or erlotinib with chemotherapy in advanced NSCLC patients in phase II clinical studies.…”

mentioning

confidence: 99%

Sequential use of vinorelbine followed by gefitinib enhances the antitumor effect in NSCLC cell lines poorly responsive to reversible EGFR tyrosine kinase inhibitors

Bello

Alama

Barletta

et al. 2015

Intl Journal of Cancer

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Preclinical studies have suggested that combining cytotoxic agents with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) to treat EGFR-mutated tumors may increase their inhibitory effect depending on the order of drug administration. The antitumor efficacy of different treatment sequences using vinorelbine (VNB) and gefitinib (GEF) was investigated both in vitro and in vivo in non-small cell lung cancer (NSCLC) cell lines with the rationale of potentially translating these findings into the clinical setting. The EGFR-wild-type A549 and the EGFR-mutated (exon 21 L858R/exon 20 T790M) H1975 cell lines were treated as follows: GEF followed by VNB, VNB followed by GEF and the two drugs applied individually or concurrently. Results in vitro demonstrated that the sequence of VNB followed by GEF was significantly more active than singleagent treatments. The expression of activated EGFR and its downstream pathway genes indicated that the increased cytotoxic effect of the VNB and GEF treatment sequence was accompanied by inhibition of EGFR, AKT and ERK1/2. Moreover, the increased inhibition of tumor growth after treatment with VNB followed by GEF was also confirmed in CD1-nude mice that were xenotransplanted with H1975 cells (p < 0.0001). This effect was paralleled by a corresponding decrease in cancer glucose consumption, as assessed by micro-positron emission tomography scans (p < 0.05). These preclinical findings in NSCLC cell lines, which are poorly responsive to EGFR-TKIs, demonstrated that the sequential treatment of VNB followed by GEF induced a significant antitumor effect, which supports the translation of this treatment schedule into a clinical setting.Lung cancer is the leading cause of cancer-related mortality and causes more than a million deaths per year. Non-small cell lung cancer (NSCLC) accounts for >85% of all lung cancers, and the majority of patients are already at an advanced stage of disease by the time of diagnosis. 1 The prognosis of patients affected by advanced disease is very poor, with a 5-year survival rate of 20%. Platinum-based chemotherapy is the standard of care for patients who do not exhibit either activating mutations of EGFR or the translocation of ALK. The most common treatment regimen involves using a platinum derivate in combination with either a thirdgeneration drug (e.g., vinorelbine, gemcitabine, paclitaxel, docetaxel, pemetrexed) or a monoclonal antibody (e.g., bevacizumab). 2,3 Vinorelbine (VNB) arrests proliferating cells in the G2/M phase of the cell cycle by inhibiting the polymerization of tubulin and inducing the de-polymerization of

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Concurrent use of vinorelbine and gefitinib induces supra-additive effect in head and neck squamous cell carcinoma cell lines

Abstract: This finding is encouraging as a proof of the possible benefit of combing an EGFR targeting compound with a cell cycle specific drug and warrants further studies of available combinations in vitro.

Cited by 13 publications

References 36 publications

Studies on the inhibition of feline EGFR in squamous cell carcinoma: Enhancement of radiosensitivity and rescue of resistance to small molecule inhibitors

Studies on the inhibition of feline EGFR in squamous cell carcinoma: Enhancement of radiosensitivity and rescue of resistance to small molecule inhibitors

Implementation of the NCI-60 Human Tumor Cell Line Panel to Screen 2260 Cancer Drug Combinations to Generate >3 Million Data Points Used to Populate a Large Matrix of Anti-Neoplastic Agent Combinations (ALMANAC) Database

Sequential use of vinorelbine followed by gefitinib enhances the antitumor effect in NSCLC cell lines poorly responsive to reversible EGFR tyrosine kinase inhibitors

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