Gefitinib Enhances the Antitumor Activity and Oral Bioavailability of Irinotecan in Mice

Stewart, Clinton F.; Leggas, Markos; Schuetz, John D.; Panetta, John C.; Cheshire, Pamela J.; Peterson, Jennifer K.; Daw, Najat C.; Jenkins, Jesse J.; Gilbertson, Richard J.; Germain, Glen S.; Harwood, Franklin C.; Houghton, Peter J.

doi:10.1158/0008-5472.can-04-0096

Cited by 186 publications

(169 citation statements)

References 30 publications

(24 reference statements)

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“…Gefitinib was able to reverse resistance and enhance cytotoxicity of well-known BCRP/P-gp substrates, such as topotecan, mitoxantrone, irinotecan, and its active metabolite SN-38, in BCRP-or P-gp-overexpressing cells (8 -12). Oral gefitinib has been reported to increase the oral bioavailability of irinotecan and topotecan (6,13) and to enhance the central nervous system penetration of topotecan in mice (14). Other studies support the hypothesis that gefitinib is a substrate for BCRP (7,15,16) and a functional variant of ABCG2 (BCRP) has recently been associated with greater gefitinib accumulation in humans, thus supporting the hypothesis that BCRP expression and activity may affect the pharmacokinetics of gefitinib (16).…”

Section: Introductionmentioning

confidence: 79%

Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition inin vitroandin vivopharmacokinetic studies employing Bcrp1−/−/Mdr1a/1b−/− (triple-knockout) and wild-type mice

Marchetti¹,

Vries

Buckle

et al. 2008

Molecular Cancer Therapeutics

183

129

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We tested whether erlotinib hydrochloride (Tarceva,, an orally active epidermal growth factor receptor tyrosine kinase inhibitor, is a substrate for the ATP-binding cassette drug transporters P-glycoprotein (Pgp; MDR1, ABCB1), breast cancer resistance protein (BCRP; ABCG2), and multidrug resistance protein 2 (MRP2; ABCC2) in vitro and whether P-gp and BCRP affect the oral pharmacokinetics of erlotinib hydrochloride in vivo. In vitro cell survival, drug transport, accumulation, and efflux of erlotinib were done using Madin-Darby canine kidney II [MDCKII; wild-type (WT), MDR1, Bcrp1, and MRP2] and LLCPK (WT and MDR1) cells and monolayers as well as the IGROV1 and the derived human BCRP-overexpressing T8 cell lines. In vivo, the pharmacokinetics of erlotinib after p.o. and i.p. administration was studied in Bcrp1/Mdr1a/1b -/-(triple-knockout) and WT mice. In vitro, erlotinib was actively transported by P-gp and BCRP/Bcrp1. No active transport of erlotinib by MRP2 was observed. In vivo, systemic exposure (P = 0.01) as well as bioavailability of erlotinib after oral administration (5 mg/kg) were statistically significantly increased in Bcrp1/Mdr1a/1b -/-knockout mice (60.4%) compared with WT mice (40.0%; P = 0.02). Conclusion: Erlotinib is transported efficiently by P-gp and BCRP/Bcrp1 in vitro. In vivo, absence of P-gp and Bcrp1 significantly affected the oral bioavailability of erlotinib. Possible clinical consequences for drug-drug and drug-herb interactions in patients in the gut between P-gp/BCRP-inhibiting substrates and oral erlotinib need to be addressed.

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Section: Introductionmentioning

confidence: 79%

Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition inin vitroandin vivopharmacokinetic studies employing Bcrp1−/−/Mdr1a/1b−/− (triple-knockout) and wild-type mice

Marchetti¹,

Vries

Buckle

et al. 2008

Molecular Cancer Therapeutics

183

129

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“…TKIs also interact with ABCG2 that can modify ADME-Tox profile of ABCG2 substrates. Gefitinib enhanced the oral bioavailability of irinotecan and topotecan, and increased their apparent bioavailability and decreased systemic clearance in mice [215,216] . Therefore, studies are needed that investigate the exact type of interactions between TKIs and cytotoxic drugs [95,208,209] .…”

Section: Tkis As Abcg2 Inhibitor or Substratementioning

confidence: 99%

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

Jaramillo¹,

Saig²,

Cloos³

et al. 2018

CDR

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P-glycoprotein (ABCB1), multidrug resistance protein-1 (ABCC1) and breast cancer resistance protein (ABCG2) belong to the ATP-binding cassette (ABC) superfamily of proteins that play an important physiological role in protection of the body from toxic xenobiotics and endogenous metabolites. Beyond this, these transporters determine the toxicity profile of many drugs, and confer multidrug resistance (MDR) in cancer cells associated with a poor treatment outcome of cancer patients.It has long been hypothesized that inhibition of ABC drug efflux transporters will increase drug accumulation and thereby overcome MDR, but until now no approved inhibitor of these transporters is available in the clinic. In this review we present molecular strategies to overcome this type of drug resistance and discuss for each of these strategies their promising value or indicate underlying reasons for their limited success.

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“…For example, the EGFR tyrosine kinase inhibitor gefitinib also inhibits BCRP and Pgp (130,136). Combining gefitinib (or other similar compounds such as erlotinib) with topotecan or irinotecan can take advantage of the cytostatic effect of gefitinib in addition to its ability to increase tumor levels of cytotoxic compounds.…”

Section: Discussionmentioning

confidence: 99%

“…Pharmacokinetically guided topotecan in combination with other agents (e.g., etoposide (184), cyclophosphamide (3), vincristine (185), and gefitinib (130,136)) may be an effective approach to improve long-term survival in high-risk neuroblastoma and other pediatric cancers. In evaluating these combinations, it will be important to use appropriate drug sequences, schedules, dosages, and systemic exposures in order to minimize host toxicity and maximize anti-tumor response.…”

Section: Discussionmentioning

confidence: 99%

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The Role of Multi-Drug Resistance Associated Protein 4 and P-glycoprotein in Resistance of Neuroblastoma to Topotecan and Irinotecan

Turner¹

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Clinton Stewart for his guidance and support. I will always appreciate his patience, the numerous opportunities he has provided, and all of the time he has spent teaching me. iii Abstract High-risk neuroblastoma presents a significant therapeutic challenge because the 5-year survival rate remains less than 30% despite the use of surgery, multi-agent chemotherapy, radiation, and autologous bone marrow transplant. Novel therapeutic modalities are under development. The camptothecin analogs topotecan and irinotecan have been identified as successful cytotoxic agents. For topotecan, pharmacokinetically guided dosing to achieve a systemic exposure associated with preclinical anti-tumor activity in neuroblastoma xenograft models is feasible and has elicited favorable responses in children with high-risk neuroblastoma. However, some children with highrisk disease did not respond to the putatively effective topotecan systemic exposure.These children represent a subset of the disease intrinsically resistant to topotecan.Furthermore, mRNA expression of the adenosine triphosphate (ATP)-binding cassette (ABC) transporters P-glycoprotein (Pgp) and multidrug resistance associated protein 1 (MRP1), which efflux many drugs used in neuroblastoma therapy, has been implicated in poor outcome in neuroblastoma. Therefore, the purpose of our studies was to determine the role of ABC transport protein expression in neuroblastoma resistance to the camptothecin analogs topotecan and irinotecan. The results of the in vitro studies demonstrate that MRP4 and Pgp confer resistance to topotecan and SN-38. In the xenograft studies, MRP4 expression was associated with failure to respond to topotecan. However, this phenotype was not recapitulated in children treated with topotecan. These results may be confounded by small sample size and timing of sample acquisition. Further investigation of the role of ABC transporters in children with neuroblastoma who receive either topotecan or irinotecan may be warranted. In addition to the camptothecin analogs, patients will receive other drugs effluxed by the ABC transporters (e.g., doxorubicin, vincristine, etoposide, and cyclophosphamide). Therefore, analyzing ABC transporter expression by immunohistochemistry in diagnostic tumor specimens may help to select agents not subject to efflux by ABC transporters expressed in the tumor. However, eliminating drugs effluxed by ABC transporters from the treatment regimen creates a potential gap in therapy and may reduce drug intensity. Therefore, further rational design and development of drugs that evade ABC transporter-mediated efflux, and potentially other resistance mechanisms in neuroblastoma, is also warranted.

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Gefitinib Enhances the Antitumor Activity and Oral Bioavailability of Irinotecan in Mice

Cited by 186 publications

References 30 publications

Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition inin vitroandin vivopharmacokinetic studies employing Bcrp1−/−/Mdr1a/1b−/− (triple-knockout) and wild-type mice

Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition inin vitroandin vivopharmacokinetic studies employing Bcrp1−/−/Mdr1a/1b−/− (triple-knockout) and wild-type mice

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

The Role of Multi-Drug Resistance Associated Protein 4 and P-glycoprotein in Resistance of Neuroblastoma to Topotecan and Irinotecan

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