Tumor-specific expression of the novel cytochrome P450 enzyme, CYP2W1

Karlgren, Maria; Gomez, Alvaro; Stark, Katarina; Svärd, Jenny; Rodríguez‐Antona, Cristina; Oliw, Ernst H.; Bernal, María Luisa; Cajal, Santiago Ramón y; Johansson, Inger; Ingelman‐Sundberg, Magnus

doi:10.1016/j.bbrc.2005.12.200

Cited by 96 publications

(124 citation statements)

References 29 publications

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“…CYP2W1, however, has recently been hailed as a tumour-specific P450 [21], with no or very low levels of CYP2W1 mRNA and protein found in normal adult tissues, so it was unexpected to find that mRNA expression of this enzyme in normal tissue was more frequent than in tumour specimens. The low prevalence of CYP1A1 mRNA expression found in this analysis is in agreement with previous results reporting lower frequency of CYP1A1 expression in tumour as compared to normal tissue [22].…”

Section: Discussionmentioning

confidence: 99%

Drug metabolism-related genes as potential biomarkers: analysis of expression in normal and tumour breast tissue

Martínez

Kennedy

Doolan

et al. 2007

Breast Cancer Res Treat

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The complex role of drug metabolism-related enzymes and their possible influence in cancer development, treatment and outcome has not yet been completely elucidated. There is evidence that these enzymes can activate certain environmental procarcinogens to more toxic derivatives and thus a role has been proposed for them in carcinogenesis. The fact that they can also inactivate a number of chemotherapeutic drugs has raised the possibility of these enzymes influencing the sensitivity of tumour cells to anticancer agents. In this report, we analyse the expression of drug metabolism-related genes within a whole genome microarray study of 104 breast cancer and 17 normal breast specimens. Kaplan-Meier survival curves, Chi-squared, and Cox Regression analyses were used to identify associations between expression of gene transcripts and patients' clinicopathological and survival data. Our results show that several of these genes are significantly expressed in both normal and tumour tissue; in many cases, expression is altered in the tumour specimens as compared to normal breast tissue. Moreover, expression of ARNT2 and GST A1 was correlated with prognosis. Kaplan-Meier analysis showed expression of ARNT2 mRNA to correlate significantly with favourable disease outcome for patients, in terms of both their disease-free survival (P = 0.0094) and overall survival (P = 0.0018) times from diagnosis, while detection of GST A1 mRNA correlated with shortened disease-free survival (P = 0.0131) and overall survival (P = 0.0028). Multivariate analysis indicated GST A1 expression to be an independent prognostic factor for overall survival (P = 0.045). Our results suggest a possible use of ARNT2 and GST A1 as prognostic breast cancer biomarkers.

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Section: Discussionmentioning

confidence: 99%

Drug metabolism-related genes as potential biomarkers: analysis of expression in normal and tumour breast tissue

Martínez

Kennedy

Doolan

et al. 2007

Breast Cancer Res Treat

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“…In addition, elevated expression of several CYP family members, notably CYP1A1, 1B1, 2S1, and 2W1, has been shown in tumors relative to normal human tissues (10)(11)(12)(13)(14)(15), and therefore, these CYPs can be viewed as molecular targets for the development of new tumor-selective therapeutic strategies (10,16). In this regard, a potential approach for bladder cancer is to use the oxidation functionality of CYP1A1 to restore potent toxicity to an inactivated chemotherapeutic selectively within the tumor, thereby facilitating reduced systemic toxicity and a consequent improved therapeutic index.…”

Section: Introductionmentioning

confidence: 99%

Antitumor Activity of a Duocarmycin Analogue Rationalized to Be Metabolically Activated by Cytochrome P450 1A1 in Human Transitional Cell Carcinoma of the Bladder

Sutherland

Gill

Loadman

et al. 2013

Molecular Cancer Therapeutics

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We identify cytochrome P450 1A1 (CYP1A1) as a target for tumor-selective drug development in bladder cancer and describe the characterization of ICT2700, designed to be metabolized from a prodrug to a potent cytotoxin selectively by CYP1A1. Elevated CYP1A1 expression was shown in human bladder cancer relative to normal human tissues. RT112 bladder cancer cells, endogenously expressing CYP1A1, were selectively chemosensitive to ICT2700, whereas EJ138 bladder cells that do not express CYP1A1 were significantly less responsive. Introduction of CYP1A1 into EJ138 cells resulted in 75-fold increased chemosensitivity to ICT2700 relative to wild-type EJ138. Negligible chemosensitivity was observed in ICT2700 in EJ138 cells expressing CYP1A2 or with exposure of EJ138 cells to CYP1B1-or CYP3A4-generated metabolites of ICT2700. Chemosensitivity to ICT2700 was also negated in EJ138-CYP1A1 cells by the CYP1 inhibitor a-naphthoflavone. Furthermore, ICT2700 did not induce expression of the AhR-regulated CYP1 family, indicating that constitutive CYP1A1 expression is sufficient for activation of ICT2700. Consistent with the selective activity by CYP1A1 was a time and concentration-dependent increase in g-H2AX protein expression, indicative of DNA damage, associated with the activation of ICT2700 in RT112 but not EJ138 cells. In mice-bearing CYP1A1-positive and negative isogenic tumors, ICT2700 administration resulted in an antitumor response only in the CYP1A1-expressing tumor model. This antitumor response was associated with detection of the CYP1A1-activated metabolite in tumors but not in the liver. Our findings support the further development of ICT2700 as a tumor-selective treatment for human bladder cancers.

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“…Only 10/41 (24.4%) OSCC samples showed up-regulated of CYP2W1 expression. Meanwhile, other studies showed CYP2W1 over-expression in gastric cancer (50.0%), colon cancer (78.0%) and adrenal tumour (75.0%) compared to normal tissue (Aung et al, 2006;Karlgren et al, 2006). An immunohistochemical study in colorectal cancer showed that CYP2W1 expression was associated with tumour staging and patients with higher CYP2W1 expression had worse clinical outcome in 5 and 10 year survival (Edler et al, 2009;Stenstedt et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

KRT13, FAIM2 and CYP2W1 mRNA Expression in Oral Squamous Cell Carcinoma Patients with Risk Habits

Hartanto¹,

Karen-Ng²,

Vincent‐Chong³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Tumor-specific expression of the novel cytochrome P450 enzyme, CYP2W1

Cited by 96 publications

References 29 publications

Drug metabolism-related genes as potential biomarkers: analysis of expression in normal and tumour breast tissue

Drug metabolism-related genes as potential biomarkers: analysis of expression in normal and tumour breast tissue

Antitumor Activity of a Duocarmycin Analogue Rationalized to Be Metabolically Activated by Cytochrome P450 1A1 in Human Transitional Cell Carcinoma of the Bladder

KRT13, FAIM2 and CYP2W1 mRNA Expression in Oral Squamous Cell Carcinoma Patients with Risk Habits

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