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Whole-genome approach implicates CD44 in cellular resistance to carboplatin.

Shukla SJ, Duan S, Wu X, Badner JA, Kasza K, Dolan ME - Hum. Genomics (2009)

Bottom Line: We further analysed the IC(50) phenotype with a linkage-directed association analysis using 71 unrelated HapMap and Perlegen cell lines and identified 18 single nucleotide polymorphisms within eight genes that were significantly associated with the carboplatin IC(50) (p < 3.6 x 10(-5); false discovery rate <5 per cent).Next, we performed linear regression on the baseline expression and carboplatin IC(50) values of the eight associated genes, which identified the most significant correlation between CD44 expression and IC(50) (r(2)= 0.20; p = 6 x 10(-4)).Knockdown of CD44 expression through small interfering RNA resulted in increased cellular sensitivity to carboplatin (p < 0.01).

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.

ABSTRACT
Carboplatin is a chemotherapeutic agent used in the management of many cancers, yet treatment is limited by resistance and toxicities. To achieve a better understanding of the genetic contribution to carboplatin resistance or toxicities, lymphoblastoid cell lines from 34 large Centre d'Etude du Polymorphisme Humain pedigrees were utilised to evaluate interindividual variation in carboplatin cytotoxicity. Significant heritability, ranging from 0.17-0.36 (p = 1 x 10(-7) to 9 x 10(-4)), was found for cell growth inhibition following 72-hour treatment at each carboplatin concentration (10, 20, 40 and 80 microM) and IC(50) (concentration for 50 per cent cell growth inhibition). Linkage analysis revealed 11 regions with logarithm of odds (LOD) scores greater than 1.5. The highest LOD score on chromosome 11 (LOD = 3.36, p = 4.2 x 10(-5)) encompasses 65 genes within the 1 LOD confidence interval for the carboplatin IC 50 . We further analysed the IC(50) phenotype with a linkage-directed association analysis using 71 unrelated HapMap and Perlegen cell lines and identified 18 single nucleotide polymorphisms within eight genes that were significantly associated with the carboplatin IC(50) (p < 3.6 x 10(-5); false discovery rate <5 per cent). Next, we performed linear regression on the baseline expression and carboplatin IC(50) values of the eight associated genes, which identified the most significant correlation between CD44 expression and IC(50) (r(2)= 0.20; p = 6 x 10(-4)). The quantitative real-time polymerase chain reaction further confirmed a statistically significant difference in CD44 expression levels between carboplatin-resistant and -sensitive cell lines (p = 5.9 x 10(-3)). Knockdown of CD44 expression through small interfering RNA resulted in increased cellular sensitivity to carboplatin (p < 0.01). Our whole-genome approach using molecular experiments identified CD44 as being important in conferring cellular resistance to carboplatin.

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Chemical structure of carboplatin.
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Figure 1: Chemical structure of carboplatin.

Mentions: The antitumour effects of platinating agents have contributed significantly to the clinical management of a variety of cancers, including ovarian, head and neck, and non-small cell lung carcinomas [1,2]. These agents exert their antitumour activity by binding preferentially to the N-7 positions of adenine and guanine of DNA, resulting in the formation of intra- and inter-strand cross-links [1]. Cisplatin and carboplatin (Figure 1) have similar mechanisms of action; differences in potency between the two drugs relate to different aquation rates. Although cisplatin has had a major clinical impact, carboplatin, with its more stable leaving group, was developed as a less toxic analogue that retained its antitumor activity [2]. In 1989, Food and Drug Administration approval was granted for a carboplatin-based regimen as the standard of care for ovarian cancer [2]. As seen with cisplatin, intrinsic and/or acquired resistance, as well as toxicities, associated with carboplatin are major limitations of this drug [1,3,4]. Carboplatin resistance may be multi-factorial, consisting of increased efflux from the cell, drug inactivation, increased DNA repair and evasion of apoptosis [5,6]. Candidate genes that may be involved in resistance to carboplatin are illustrated in the platinum-based pathway on the PharmGKB website http://www.pharmgkb.org.


Whole-genome approach implicates CD44 in cellular resistance to carboplatin.

Shukla SJ, Duan S, Wu X, Badner JA, Kasza K, Dolan ME - Hum. Genomics (2009)

Chemical structure of carboplatin.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2683878&req=5

Figure 1: Chemical structure of carboplatin.
Mentions: The antitumour effects of platinating agents have contributed significantly to the clinical management of a variety of cancers, including ovarian, head and neck, and non-small cell lung carcinomas [1,2]. These agents exert their antitumour activity by binding preferentially to the N-7 positions of adenine and guanine of DNA, resulting in the formation of intra- and inter-strand cross-links [1]. Cisplatin and carboplatin (Figure 1) have similar mechanisms of action; differences in potency between the two drugs relate to different aquation rates. Although cisplatin has had a major clinical impact, carboplatin, with its more stable leaving group, was developed as a less toxic analogue that retained its antitumor activity [2]. In 1989, Food and Drug Administration approval was granted for a carboplatin-based regimen as the standard of care for ovarian cancer [2]. As seen with cisplatin, intrinsic and/or acquired resistance, as well as toxicities, associated with carboplatin are major limitations of this drug [1,3,4]. Carboplatin resistance may be multi-factorial, consisting of increased efflux from the cell, drug inactivation, increased DNA repair and evasion of apoptosis [5,6]. Candidate genes that may be involved in resistance to carboplatin are illustrated in the platinum-based pathway on the PharmGKB website http://www.pharmgkb.org.

Bottom Line: We further analysed the IC(50) phenotype with a linkage-directed association analysis using 71 unrelated HapMap and Perlegen cell lines and identified 18 single nucleotide polymorphisms within eight genes that were significantly associated with the carboplatin IC(50) (p < 3.6 x 10(-5); false discovery rate <5 per cent).Next, we performed linear regression on the baseline expression and carboplatin IC(50) values of the eight associated genes, which identified the most significant correlation between CD44 expression and IC(50) (r(2)= 0.20; p = 6 x 10(-4)).Knockdown of CD44 expression through small interfering RNA resulted in increased cellular sensitivity to carboplatin (p < 0.01).

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.

ABSTRACT
Carboplatin is a chemotherapeutic agent used in the management of many cancers, yet treatment is limited by resistance and toxicities. To achieve a better understanding of the genetic contribution to carboplatin resistance or toxicities, lymphoblastoid cell lines from 34 large Centre d'Etude du Polymorphisme Humain pedigrees were utilised to evaluate interindividual variation in carboplatin cytotoxicity. Significant heritability, ranging from 0.17-0.36 (p = 1 x 10(-7) to 9 x 10(-4)), was found for cell growth inhibition following 72-hour treatment at each carboplatin concentration (10, 20, 40 and 80 microM) and IC(50) (concentration for 50 per cent cell growth inhibition). Linkage analysis revealed 11 regions with logarithm of odds (LOD) scores greater than 1.5. The highest LOD score on chromosome 11 (LOD = 3.36, p = 4.2 x 10(-5)) encompasses 65 genes within the 1 LOD confidence interval for the carboplatin IC 50 . We further analysed the IC(50) phenotype with a linkage-directed association analysis using 71 unrelated HapMap and Perlegen cell lines and identified 18 single nucleotide polymorphisms within eight genes that were significantly associated with the carboplatin IC(50) (p < 3.6 x 10(-5); false discovery rate <5 per cent). Next, we performed linear regression on the baseline expression and carboplatin IC(50) values of the eight associated genes, which identified the most significant correlation between CD44 expression and IC(50) (r(2)= 0.20; p = 6 x 10(-4)). The quantitative real-time polymerase chain reaction further confirmed a statistically significant difference in CD44 expression levels between carboplatin-resistant and -sensitive cell lines (p = 5.9 x 10(-3)). Knockdown of CD44 expression through small interfering RNA resulted in increased cellular sensitivity to carboplatin (p < 0.01). Our whole-genome approach using molecular experiments identified CD44 as being important in conferring cellular resistance to carboplatin.

Show MeSH
Related in: MedlinePlus