Idoxifene versus tamoxifen: a randomized comparison in postmenopausal patients with metastatic breast cancer

Arpino, Grazia; Krishnan, Mridula; Dinesh, C. Doval; Bardou, Valérie‐Jeanne; Clark, Gary M.; Elledge, Richard M.

doi:10.1093/annonc/mdg097

Cited by 34 publications

(14 citation statements)

References 31 publications

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“…Tamoxifen was first approved in 1977 by the U.S. FDA for the treatment of metastatic breast cancer and breast cancer. Other triphenylethylene SERMs, analogs of tamoxifen, have been studied for breast cancer prevention and/or treatment, including droloxifene (3-hydroxytamoxifen) [269][270][271], idoxifene (pyrrolidino-4-iodotamoxifen) [272][273][274][275], and ospemifene [276].…”

Section: Tamoxifenmentioning

confidence: 99%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

147

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Cytochrome P450 2C9 (CYP2C9) is one of the most abundant CYP enzymes in the human liver. CYP2C9 metabolizes more than 100 therapeutic drugs, including tolbutamide, glyburide, diclofenac, celecoxib, torasemide, phenytoin losartan, and S-warfarin). Some natural and herbal compounds are also metabolized by CYP2C9, probably leading to the formation of toxic metabolites. CYP2C9 also plays a role in the metabolism of several endogenous compounds such as steroids, melatonin, retinoids and arachidonic acid. Many CYP2C9 substrates are weak acids, but CYP2C9 also has the capacity to metabolise neutral, highly lipophilic compounds. A number of ligand-based and homology models of CYP2C9 have been reported and this has provided insights into the binding of ligands to the active site of CYP2C9. Data from the site-directed mutagenesis studies have revealed that a number of residues (e.g. Arg97, Phe110, Val113, Phe114, Arg144, Ser286, Asn289, Asp293 and Phe476) play an important role in ligand binding and determination of substrate specificity. The resolved crystal structures of CYP2C9 have confirmed the importance of these residues in substrate recognition and ligand orientation. CYP2C9 is activated by dapsone and its analogues and R-lansoprazole in a stereo-specific and substrate-dependent manner, probably through binding to the active site and inducing positive cooperativity. CYP2C9 is subject to induction by rifampin, phenobarbital, and dexamethasone, indicating the involvement of pregnane X receptor, constitutive androstane receptor and glucocorticoid receptor in the regulation of CYP2C9. A number of compounds have been found to inhibit CYP2C9 and this may provide an explanation for some clinically important drug interactions. Tienilic acid, suprofen and silybin are mechanism-based inhibitors of CYP2C9. Given the critical role of CYP2C9 in drug metabolism and the presence of polymorphisms, it is important to identify drug candidates as potential substrates, inducer or inhibitors of CYP2C9 in drug development and drug discovery scientists should develop drugs with minimal interactions with this enzyme. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships.

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Section: Tamoxifenmentioning

confidence: 99%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

147

View full text Add to dashboard Cite

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“…Morbidity was similar for both groups. The authors concluded that in postmenopausal women with metastatic breast cancer, idoxifene had similar efficacy and toxicity compared to TAM [115]. Idoxifene has not been developed further because of concerns about uterine prolapse.…”

Section: Idoxifenementioning

confidence: 99%

Estrogen Receptors as Therapeutic Targets in Breast Cancer

Ariazi¹,

Ariazi²,

Cordera³

et al. 2006

curr top med chem

126

155

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The estrogen receptor alpha (ERalpha) has proven to be the single most important target in breast cancer over the last 30 years. The use of the selective ER modulator (SERM) tamoxifen for the treatment and prevention of breast cancer has changed therapeutics. The SERM raloxifene, approved for the treatment of osteoporosis, lacks tamoxifen's increased risk for endometrial cancer and is being evaluated for the prevention of breast cancer. Other SERMs approved or under development for use against breast cancer or osteoporosis include toremifene, GW5638, GW7604 (the active metabolite of GW5638), idoxifene, lasofoxifene, arzoxifene, bazedoxifene, EM-800 and acolbifene (the active metabolite of EM-800). Aromatase inhibitors (AIs) have recently proven to be more efficacious than tamoxifen as first-line therapy, efficacious for second-line therapy (e.g. against tamoxifen-resistant disease), and useful for extended adjuvant therapy after tamoxifen. The AIs include the non-steroidal agents letrozole and anastrole, and the steroidal agent exemestane. The pure antiestrogen fulvestrant has proven to be just as effective as AIs. Other pure antiestrogens, ZK-703, ZK-253, RU 58668 and TAS-108 show great promise. The development of resistance to endocrine therapy remains a clinically important problem, and laboratory models based on human breast cancer cells grown as tumors in immune-compromised mice have led to important insights into this problem. Progesterone receptor-negative status of ER-positive breast cancers may reflect altered growth factor receptor signaling, and helps to explain why this subclass of tumors exhibits lower response rates to tamoxifen compared to cancers typed progesterone receptor-positive. Crosstalk among plasma membrane-localized ER, growth factor receptor signaling, and nuclear-localized ER provide further insights into antihormonal-resistant breast cancer.

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“…53 Idoxifene is metabolically more stable through the substitution of iodine at the 4-position of TAM and showed comparable efficacy and safety profiles as TAM, but caused the side effect of uterine prolapse and was hence stopped from further development. 54 The phosphate miproxifene, was also proven inferior to TAM and was thus canceled from further development. 55 Nafoxidine and its saturated form lasofoxifene are fixed ring analogs of OHT, whereby the isomerization to the cis-isomer is prohibited.…”

Section: Comparisons Of Selected Sermsmentioning

confidence: 99%

Modification of the anticancer drug tamoxifen to avoid CYP2D6 polymorphism

Gao

Sun

et al. 2013

Can. J. Chem.

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The prodrug tamoxifen (TAM) is the most widely used drug to treat breast cancer, and is metabolised to the active 4-hydroxy derivatives dominantly by hepatic CYP2D6. However, the application to patients with different polymorphic CYP2D6 has been under debate, because the efficacy of TAM is suspected to be suppressed in patients who have diminished CYP2D6 activity, resulting in inadequate active metabolites. We here propose modified structures, such as 4-methylTAM, which is highly possible to be activated by CYP3A, the most abundant CYP isoforms in the liver, whereby the genetic polymorphism of CYP2D6 is avoided. The diversity of CYP catalyzed metabolic paths for TAM and its derivatives are studied by quantum chemistry calculations on the reaction energies of the initial H atom abstraction steps. The ability of forming DNA adducts is compared through the formation enthalpy of the carbocation intermediate. The results suggest that the modified structures are safe with regard to forming DNA adducts and may be used as prodrugs in a wide range of patients, due to CYP3A, rather than CYP2D6, mediated activation. Résumé :Le tamoxifène (TAM), la substance médicamenteuse la plus utilisée pour traiter le cancer du sein, est un promédica-ment qui est métabolisé en dérivés 4-hydroxylés actifs principalement par l'enzyme hépatique CYP2D6. Cependant son administration à des patientes présentant différents polymorphismes du CYP2D6 a fait l'objet de débats, parce que l'on soupçonne une suppression de l'efficacité du TAM chez celles dont l'activité du CYP2D6 est réduite, ce qui donne une production inadéquate de métabolites actifs. Nous proposons ici des structures modifiées, comme le 4-méthylTAM, qui est hautement activable par le CYP3A, l'isoforme CYP la plus abondante dans le foie, afin d'éviter le polymorphisme génétique du CYP2D6. Nous étudions les divers chemins de métabolisation du TAM et de ses dérivés catalysée par les CYP au moyen de calculs de chimie quantique portant sur les énergies de réaction des étapes d'abstraction de l'atome d'hydrogène initial. Nous comparons la capacité de former des adduits d'ADN en nous fondant sur l'enthalpie de formation du carbocation intermédiaire. Les résultats donnent à penser que les structures modifiées sont inoffensives en ce qui concerne la formation d'adduits d'ADN et peuvent être utilisées comme promédicaments chez une grande variété de patientes, en raison de leur activation par le CYP3A plutôt que le CYP2D6. [Traduit par la Rédaction]

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Idoxifene versus tamoxifen: a randomized comparison in postmenopausal patients with metastatic breast cancer

Abstract: Idoxifene was both active and well tolerated in postmenopausal women with metastatic breast cancer. Idoxifene had similar efficacy and toxicity to tamoxifen in this randomized comparison.

Cited by 34 publications

References 31 publications

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Estrogen Receptors as Therapeutic Targets in Breast Cancer

Modification of the anticancer drug tamoxifen to avoid CYP2D6 polymorphism

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