Pharmacogenomics of Sex Difference in Chemotherapeutic Toxicity

Wang, Jeffrey; Huang, Ying

doi:10.2174/157016307781115485

Cited by 48 publications

(18 citation statements)

References 73 publications

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“…Sex-related differences at the genetic and molecular levels also affect the differences in the degree of drug response ( Wang and Huang, 2007 ). Although sex disparities in the incidence and mortality of cancer have been observed for a variety of cancers, chemotherapy has been conducted independent of sex ( Keitt et al ., 2004 ; Becker et al ., 2005 ; Zucker and Beery, 2010 ).…”

Section: Sex Differences In Efficacy and Toxicity Of Chemotherapymentioning

confidence: 99%

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Sex Differences in Cancer: Epidemiology, Genetics and Therapy

Kim

Lim

Moon

2018

Biomolecules & Therapeutics

253

165

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The incidence and mortality of various cancers are associated with sex-specific disparities. Sex differences in cancer epidemiology are one of the most significant findings. Men are more prone to die from cancer, particularly hematological malignancies. Sex difference in cancer incidence is attributed to regulation at the genetic/molecular level and sex hormones such as estrogen. At the genetic/molecular level, gene polymorphism and altered enzymes involving drug metabolism generate differences in cancer incidence between men and women. Sex hormones modulate gene expression in various cancers. Genetic or hormonal differences between men and women determine the effect of chemotherapy. Until today, animal studies and clinical trials investigating chemotherapy showed sex imbalance. Chemotherapy has been used without consideration of sex differences, resulting in disparity of efficacy and toxicity between sexes. Based on accumulating evidence supporting sex differences in chemotherapy, all clinical trials in cancer must incorporate sex differences for a better understanding of biological differences between men and women. In the present review, we summarized the sex differences in (1) incidence and mortality of cancer, (2) genetic and molecular basis of cancer, (3) sex hormones in cancer incidence, and (4) efficacy and toxicity of chemotherapy. This review provides useful information for sex-based chemotherapy and development of personalized therapeutic strategies against cancer.

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Section: Sex Differences In Efficacy and Toxicity Of Chemotherapymentioning

confidence: 99%

“…Accumulating evidence shows sex-specific differences in toxicity and efficacy of chemotherapy ( Tran et al ., 1998 ; Rademaker, 2001 ; Anderson, 2005 ; Bren, 2005 , Schmetzer and Flörcken, 2012 ). Especially, women experience higher adverse drug reactions to most anticancer drugs than men ( Wang and Huang, 2007 ).…”

Section: Introductionmentioning

confidence: 99%

Sex Differences in Cancer: Epidemiology, Genetics and Therapy

Kim

Lim

Moon

2018

Biomolecules & Therapeutics

253

165

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“…26) Drug metabolism and elimination are sex-dependent and influenced by sex hormones, menopause, and menstruation. 27) Sex-selective toxicity may be influenced by sex-dependent disparities in pharmacokinetic and pharmacodynamics of several drugs. 28) The different toxicity between male and female may be associated with different pharmacokinetics to sex.…”

Section: Discussionmentioning

confidence: 99%

“…28) The different toxicity between male and female may be associated with different pharmacokinetics to sex. 27) The detailed molecular mechanism of 5-FU-induced side effects based on sex-specific differences between men and women remains to be further elucidated. The reason why we used a xenograft animal model in our study was because there was a report examined the sex difference by 5-FU using male and female animals without xenograft.…”

Section: Discussionmentioning

confidence: 99%

Sex-Dependent Adverse Drug Reactions to 5-Fluorouracil in Colorectal Cancer

Lim

Kim

Lee

et al. 2019

Biological & Pharmaceutical Bulletin

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Sex-related incidence and outcomes were reported in various cancers, including colorectal cancer. 5-Fluorouracil (5-FU) is widely used as an essential chemotherapeutic agent for colorectal cancer. However, sexbased differences in 5-FU toxicity have yet to be reported in human cancer cell lines and xenograft mouse models to date. Here, we investigated, for the first time, sex-based differences in 5-FU toxicity using human colon cancer cell lines, xenograft mouse models, and Korean patients' data. Female-derived colon cancer cell lines exhibited greater 5-FU-induced cytotoxicity than male-derived colon cancer cell lines. We established two xenograft mouse models: one with a male-derived human colon cancer cell line injected into male mice (a male-xenograft model) and another involving a female-derived human colon cancer cell line injected into female mice (a female xenograft model). Treatment with 5-FU inhibited tumor growth and led to hematological toxicity in a female xenograft model more potently than in a male xenograft model. We analyzed the data obtained from Korean patients with colorectal cancer to examine sex differences in adverse drug reactions caused by 5-FU. Korean female patients with colorectal cancer who received 5-FU chemotherapy experienced more frequent adverse drug reactions including alopecia and leukopenia than male patients. Taken together, we demonstrated that female may be associated with increased risk of toxicity to 5-FU treatment in colorectal cancer based on in vitro and in vivo investigations and clinical data analysis. Our study suggests sex as an important clinical factor, which predicts induction of toxicity related to 5-FU treatment.

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“…These sex-differences have been widely demonstrated by human and animal pharmacokinetic studies (Zhu et al 2007), pharmacogenetic studies (Wang and Huang 2007), behavioral studies (Keeley et al 2013), and neuroimaging studies (Cahill 2014). Nevertheless, many gaps remain in our understanding of these sex-differences.…”

Section: Introductionmentioning

confidence: 99%

Sex difference of autosomal alleles in populations of European and African descent

et al. 2015

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In the present study, we aimed to report the individual sex-different genetic markers across autosomes in European- and African-origin populations. A total of 8,400 females and 8,081 males in 19 independent cohorts were genotyped across genomes using Illumina or Affymetrix arrays. The allele frequencies were compared between females and males in 9 non-clean cohorts (with some human disease traits) using genome-wide logistic regression and then the nominally significant associations were replicated across 10 clean cohorts (without disease traits). Meta-analysis was performed to derive the combined p values across all cohorts. We found 13 markers that were genome-wide significant (p≤5×10−8) between females and males in the meta-analysis of all cohorts of European descent, including rs7740449 at SYNE1, rs7531151 at PLD5, rs697455 at PPP1R12B, rs6745746 at LOC100128413, rs17000079 at PARM1, rs11948070 at PDE4D, rs7801825 at INSIG1, rs9551642 at MTUS2, rs2932174 at TPTE2, rs1961597 at SALL3, rs4117529 at METTL4, rs6021473 at SALL4 and rs6092466 at RAE1, and one marker, i.e., rs10145208 at PCNX, that was genome-wide significant in the meta-analysis of all cohorts of African descent. The most robust finding was rs7740449 at SYNE1, next to ESR1. We conclude that there are many sex-different markers on autosomes. These markers may be informative in differentiating females and males.

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Pharmacogenomics of Sex Difference in Chemotherapeutic Toxicity

Cited by 48 publications

References 73 publications

Sex Differences in Cancer: Epidemiology, Genetics and Therapy

Sex Differences in Cancer: Epidemiology, Genetics and Therapy

Sex-Dependent Adverse Drug Reactions to 5-Fluorouracil in Colorectal Cancer

Sex difference of autosomal alleles in populations of European and African descent

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