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. 2018 Jul 1;26(4):335–342. doi: 10.4062/biomolther.2018.103

Sex Differences in Cancer: Epidemiology, Genetics and Therapy

Hae-In Kim 1,†, Hyesol Lim 1,†, Aree Moon 1,*
PMCID: PMC6029678  PMID: 29949843

Abstract

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.

Keywords: Sex Difference, Cancer, Sex hormone, Chemotherapy

INTRODUCTION

Cancer represents a leading cause of death worldwide (Naghavi et al., 2016). Sex plays a crucial role in the incidence, disease prognosis and mortality in a variety of cancers (Siegel et al., 2016). The incidence of cancer was about 20% higher in men than in women and the mortality rate was 40% higher in men in the United States from 2009 to 2013 (Siegel et al., 2017). Sex differences influence cancer susceptibility at the genetic/molecular levels. Sex hormones also negatively or positively affect the development of various cancers. Biological specificities determine the outcome and response to therapy of cancer.

During the last decades, animal studies and clinical trials used males alone and excluded females (Keitt et al., 2004; Becker et al., 2005; Zucker and Beery, 2010). Altered sex hormones in the menstrual cycle affect the experimental results (Becker et al., 2005). In addition, the 1977 United States Food and Drug Administration guideline excluded women in clinical research due to the risk of birth defects (Merkatz et al., 1993). Similar doses were administered to men and women in clinical chemotherapy (Islam et al., 2017). 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).

This review summarized studies involving sex differences in epidemiology, sex hormones, and genetic/molecular factors. In addition, we reviewed sex-related differences in chemotherapy using anticancer agents such as 5-fluorouracil (FU), paclitaxel, doxorubicin, cisplatin, bevacizumab and rituximab. This article provides important clues and insights for the precise understanding of sex-specific differences in cancer.

SEX DIFFERENCES IN INCIDENCE AND MORTALITY OF CANCER

Growing evidence shows sex-specific differences in the incidence and mortality associated with various cancers. Prostate, lung, and colorectal cancer occur the most in males, while breast, lung, and colorectal cancer are predominant in females in the United States (Siegel et al., 2016). In addition to the incidence of cancer in sex-specific organs such as prostate and ovary, sex differences in cancers such as colon, lung, and liver have been reported (Dorak and Karpuzoglu, 2012; Torre et al., 2016). Thyroid cancer incidence is much higher in females than in males (Dorak and Karpuzoglu, 2012). Cancer incidence involving colorectal, stomach and liver cancer is higher in males than in females (Arnold et al., 2017). Furthermore, bladder cancer and leukemia have been predominantly diagnosed in males than in females (Fitzmaurice et al., 2017). In patients with colorectal cancer, women developed right-sided malignancy while men manifested the disease more on the left side (Kim et al., 2015). Right-sided colon cancer is associated with a higher severity of cancer compared with left-sided disease (Kim et al., 2015). The cause of disparity in location might be due to differences in estrogen level between men and women.

The mortality of cancer is reported to be greater in men than in women (Siegel et al., 2016). Especially, lung, colorectal and stomach cancers, which are the leading causes of cancer deaths, show higher mortality in men than in women (Siegel et al., 2016; Fitzmaurice et al., 2017). Female cancers such as breast, ovarian and uterine corpus cancer result in relatively high mortality (Siegel et al., 2016; Fitzmaurice et al., 2017). Men-specific cancers such as prostate cancer also represent prominent causes for cancer death (Siegel et al., 2016). Mortality associated with esophagus, liver, and bladder cancer is higher in men than in women (Siegel et al., 2016). Men had a 34% higher risk of death due to melanoma compared with women (Crocetti et al., 2015). Therefore, mortality from various cancer types shows sex disparity.

Lung cancer was the leading cause of cancer death in men in 20th century due to smoking (Siegel et al., 2016). Lung cancer death was decreased by reduced smoking rates and early detection and treatment from 1991 to 2012 (Siegel et al., 2016). In both sexes, mortality due to gastric cancer declined rapidly in the 1930s in U.S (Siegel et al., 2016). Although the cause of dramatic reduction is not completely understood, the control of Helicobacter pylori infection, and better methods of food preservation resulted in a reduction of mortality due to stomach cancer (Bertuccio et al., 2009; Siegel et al., 2016).

SEX DIFFERENCES IN GENETIC AND MOLECULAR BASIS OF CANCER

In genetic and molecular studies, susceptibility to disease varies across the sexes. Genetic and molecular disparities between males and females contribute to differences in the incidence of a variety of cancers. Men show a higher incidence of bladder cancer than women (Siegel et al., 2016). The lower incidence of bladder cancer in women was correlated with the sulfotransferase 1A1 (SULT1A1) Histidine (His) genotype (Zheng et al., 2003). Genetic polymorphism of SULT1A1 showed alteration from Arginine to His, which was triggered by A-to-G transition (Raftogianis et al., 1997). It was reported that the His213 allele genotype SULT1A1 significantly decreased the risk of bladder cancer exclusively in women (Zheng et al., 2003). Therefore, this gene might be associated with a protective role in women diagnosed with bladder cancer (Dorak and Karpuzoglu, 2012).

Genetic polymorphism, which is linked to drug metabolizing enzymes, influences the risk of carcinogenesis (Bolufer et al., 2007). For example, acute leukemia has a higher rate of incidence in men than in women (Bolufer et al., 2007). It was reported that men with deletion of glutathione s-methyltransferase T1 (GSTT1), which is a glutathione s-methyltransferase polymorphism, underwent phase 2 metabolism and detected frequently in acute lymphoblastic leukemia (ALL) than men with normal GSTT1 (Mannervik and Danielson, 1988; Hayes and Strange, 2000; Bolufer et al., 2007). Deletion of GSTT1 gene abrogated the enzyme activity (Arand et al., 1996).

NAD(P)H:quinone oxidoreductase 1 (NQO1) catalyzes free radical detoxification (Traver et al., 1992). NQO1 polymorphism with substitution of C to T base pair at position 609 of NQO1 decreases the activity of the enzyme (Asher et al., 2002; Fagerholm et al., 2008). NQO1 polymorphism showed a higher incidence of ALL only in males, but not in females (Bolufer et al., 2007).

Murine double minute 2 (MDM2) downregulates the expression of p53 protein, a tumor suppressor (Eliyahu et al., 1989; Bond et al., 2004). A single nucleotide polymorphism 309 (SNP 309) in MDM2 promotor increases the affinity of the transcriptional activator Sp1, which enhances the expression of MDM2 and consequently leads to attenuation of p53 pathway (Bond et al., 2004). Attenuation of p53 DNA damage response occurs in the presence of both wild-type allele of p53 and G-allele of SNP 309 (Bond et al., 2006). In addition, estrogen signaling affects the level of MDM2 (Bond et al., 2006). In the diffuse large B-cell lymphoma (DLBCL), sporadic soft-tissue sarcoma, and highly invasive estrogen receptor-positive ductal carcinoma, estrogen signaling pathway increases tumor formation directly or indirectly in women carrying the Gallele of SNP309 (Bond et al., 2006). Taken together, genetic and molecular differences might influence the disparity of the risk of cancer between men and women.

SEX DIFFERENCES IN SEX HORMONES IN CANCER INCIDENCE

Sex hormones might contribute to differences in the incidence of cancer between men and women (Do et al., 2010; Dorak and Karpuzoglu, 2012). ALL is more likely to occur in men because of limited estrogen level (Do et al., 2010). Estrogen plays a role in the inhibition of nuclear factor kappa B (NF-κB). NF-κB regulates the transcription of interferon regulatory factor 4 (IRF4) (Do et al., 2010). IRF4 is involved in the differentiation of B and T cells and is overexpressed in B-cell malignancies as a result of NF-κB hyperactivation (Do et al., 2010). IRF4 polymorphisms are related with the incidence of ALL (Do et al., 2010). Thus, a combination of intronic polymorphism of IRF4 and lack of estrogen might predispose men to leukemia.

Estrogen is linked closely to a higher rate of thyroid cancer development in women (Lee et al., 2005; Dorak and Karpuzoglu, 2012). Estrogen increases the proliferation of human thyroid papillary carcinoma cell line and promotes the expression of B-cell lymphoma-extra large (Bcl-XL), which is known as an anti-apoptotic protein (Hsu et al., 1997; Lee et al., 2005), compared with testosterone. Endogenous female sex hormone such as progestin increase excretion of bile acid, which has been suggested as a potential inducer of colon cancer (McMichael and Potter, 1980; Farhana et al., 2016). Exogenous estrogen decreased the production of secondary bile acid which is responsible for promoting malignant change in colonic epithelium (McMichael and Potter, 1980; Everson et al., 1991; Grodstein et al., 1999). Therefore, female sex hormones may play a protective role in the development of colon cancer, by decreasing the level of bile acid (McMichael and Potter, 1980; Farhana et al., 2016).

SEX DIFFERENCES IN EFFICACY AND TOXICITY OF CHEMOTHERAPY

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). Research involving animal model and clinical trials has been almost male-oriented. Accumulating evidence supports sex-related response to chemotherapeutic agents. Anticancer drugs, which represent sex differences in efficacy and toxicity, are summarized and listed in Table 1.

Table 1.

Anticancer drugs with sex differences in efficacy and toxicity

Drug Sex differences References
5-fluorouracil Clearance is higher in males than in females Milano et al., 1992
Females experienced higher toxicity (including stomatitis, leukopenia, alopecia and diarrhea) frequently and severely than males Sloan et al., 2002
Paclitaxel Females showed lower elimination than males Joerger et al., 2006
Peripheral compartment of females is saturated at lower plasma concentrations levels compared with males Joerger et al., 2006
Elimination is faster in males than in females Joerger et al., 2006
Females experienced severe leukopenia greater than males Schmetzer and Flörcken, 2012; Yamamoto et al., 2008
Females showed longer median progression-free survival than males Yamamoto et al., 2008
Doxorubicin Males have significantly higher clearance than females Dobbs et al., 1995
Females experienced higher risk of early cardiotoxicity than males following treatment with doxorubicin in childhood leukemia Lipshultz et al., 1995
Cisplatin Females experienced higher toxicities including vomiting and nausea than males Liaw et al., 2001
Male rats showed prolonged heat latency and slower motor nerve conduction than female rats Wongtawatchai et al., 2009
The half-maximal inhibitory concentration (IC50) of male cell lines was lower than that of females Huang et al., 2007
Bevacizumab Clearance was higher in males than in females Lu et al., 2008
Female experienced more severe hypertension and neutropenia, and higher rate of abdominal pain than males Brahmer et al., 2011
Females experienced higher rates of abdominal pain than males Brahmer et al., 2011
Rituximab Clearance was higher in males than in female Müller et al., 2012
Half-life of elimination in male was longer compared with females Müller et al., 2012
The better responses from treatment and outcomes were more prominent in females than in males Riihijärvi et al., 2011
Male patients had a worse progression-free survival than female patients both in diffuse large B-cell lymphoma and follicular lymphoma Riihijärvi et al., 2011
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5-FU

In the treatment of various cancers, 5-FU has been widely used as an effective chemotherapy (Longley et al., 2003). 5-FU as a pyrimidine antagonist inhibits thymidine synthase which is essential for DNA synthesis (Santi et al., 1974; Yoshioka et al., 1987; Longley et al., 2003). It has been observed that 5-FU might elicit different toxicities depending on sex (Stein et al., 1995; Sloan et al., 2002). Clearance of 5-FU is higher in male (179 l/h/m2) than in female (155 l/h/m2) (Milano et al., 1992). Low clearance of 5-FU in females can result in higher toxicity (Wang and Huang, 2007). Dihydropyrimidine dehydrogenase (DPD) breaks down 5-FU (Wasternack, 1980; Diasio and Harris, 1989; Longley et al., 2003). DPD plays a crucial role in toxicity associated with 5-FU chemotherapy (Harris et al., 1991). The activity of DPD was decreased in female and the difference in DPD activity between males and females is 15% (Etienne et al., 1994). A lower DPD activity associated with toxicity in women might be attributed to DPD deficiency syndrome (Milano et al., 1999). Reduced degradation of 5-FU in female influences therapeutic efficacy and toxicity (Mader, 2007). In 5-FU-based chemotherapy, women experimented higher toxicities, including stomatitis, leukopenia, alopecia, and diarrhea, more frequently and severely than men (Sloan et al., 2002).

Paclitaxel

Antitumor effects of paclitaxel, which inhibits depolymerization of cytoskeletal microtubules, interfere with cell division (Schiff and Horwitz, 1980; Jordan and Wilson, 2004). It was reported that female patients with solid tumors have 20% lower elimination of paclitaxel than male patients (Joerger et al., 2006). Peripheral compartments of female (0.83 mmol/l) are saturated at lower plasma concentrations compared with those of male (1.74 mmol/l) (Joerger et al., 2006). On the other hand, paclitaxel elimination is faster in male (≤0.5 h) than in female (≤1 h) (Joerger et al., 2006). In the treatment with paclitaxel combined with carboplatin, the number of female patients exhibiting toxicity such as severe leukopenia was greater than that of male patients (Yamamoto et al., 2008; Schmetzer and Flörcken, 2012). Conversely, female patients diagnosed with lung carcinoma (5.3 months) who were treated with paclitaxel combined with carboplatin showed longer median progression-free survival (PFS) rate than male patients (4.4 months) (Yamamoto et al., 2008). These sex-related differences might be explained by DNA repair, which was lower in females than in males (Wei et al., 2000). The lower DNA repair ability might affect tumor cell in female after administering cytotoxic anticancer drug and influence the prolonged PFS in female patients (Yamamoto et al., 2008).

Doxorubicin

Doxorubicin is an anthracycline DNA-damaging agent that targets the topoisomerase 2 activity and DNA intercalation (Gewirtz, 1999; Rivankar, 2014; Mitry and Edwards, 2016). Another predicted mechanism of doxorubicin generates free radicals resulting in damage to membrane and DNA of cancer cell (Gewirtz, 1999; Rivankar, 2014; Mitry and Edwards, 2016). In patients with breast cancer or lymphoma, male with normal liver function showed significantly higher doxorubicin clearance (59 l/h/m2) than female (27 l/h/m2) (Dobbs et al., 1995). Female might be an independent risk factor increasing the toxicity of doxorubicin such as cardiac abnormalities (Lipshultz et al., 1991, 1995). Exposure to doxorubicin in childhood leukemia in females increases the risk of early cardiotoxicity compared with in males (Lipshultz et al., 1995). P-glycoprotein, which is expressed by multidrug resistance protein 1 gene, is a drug transporter that pumps many foreign substances out of cells (Schuetz et al., 1995). Expression of p-glycoprotein in males is 2-fold higher than in females (Schuetz et al., 1995). In females, doxorubicin and doxorubicinol, which is a doxorubicin metabolite, accumulate following a reduced expression of p-glycoprotein and leads to cardiotoxicity (van Asperen et al., 1999).

Disparities in drug metabolizing enzymes between men and women might have an impact on drug metabolism or volume of distribution of doxorubicin (Frisancho, 1974; Ley et al., 1992; Lipshultz et al., 1995). Doxorubicin is not accumulated at a higher concentration in adipose tissue (Rodvold et al., 1988, Lipshultz et al., 1995). The higher proportion of fat in female patients might lead to a higher concentration of doxorubicin in non-adipose tissues such as heart in women even if men and women carried the same body surface areas.

Cisplatin

Cisplatin as cis-diamminedichloroplatinum (II) exhibits covalent bonding with adjacent guanines located in the major groove of DNA (Bellon et al., 1991). This intra-strand cross-links with DNA result in distortion of DNA and antitumor effects. Female patients treated with cisplatin-based therapy show substantially higher toxicities such as vomiting and nausea than males (Liaw et al., 2001). Male rats treated with cisplatin show general toxicity, prolonged thermal latency and slow motor nerve conduction velocity than female rats (Wongtawatchai et al., 2009). Sex-dependent difference may not be related to lower body size in females but physiological variables such as distinct body composition and metabolic activity (Wongtawatchai et al., 2009). In the Yoruban population which comprised of African descent, male-derived cell lines demonstrated higher sensitivity to cisplatin than female-derived cell lines (Huang et al., 2007). The half-maximal inhibitory concentration (IC50) of cisplatin in male-derived cell lines was lower than that in female-derived cell lines (Huang et al., 2007).

Bevacizumab

Bevacizumab is a monoclonal antibody, which blocks vascular endothelial growth factor and inhibits angiogenesis in tumors (Ferrara, 2004; Sandler et al., 2006). It was reported that clearance of bevacizumab was 26% higher in male patients with solid tumors than in female patients, which is associated with a greater muscle mass in males than in females (Lu et al., 2008). Chemotherapy with bevacizumab for non-small cell lung cancer led to more severe hypertension and neutropenia and higher rate of abdominal pain in female patients than in male patients (Brahmer et al., 2011).

Rituximab

Rituximab is a monoclonal antibody, which targets CD20 on B cell surface. It is used to treat autoimmune diseases and hematological cancers such as non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. The clearance of rituximab is higher in male patients (8.21 ml/h) with DLBCL than in female patients (12.68 ml/h) and the elimination half-life in male patients (t1/2β=30.7 days) is longer compared with female patients (t1/2β=24.7 days) (Müller et al., 2012). In the DLBCL treatment with rituximab, the better treatment outcomes were more prominent in females than in males (Riihijärvi et al., 2011). GSTT1 deletion might be related to adverse prognosis only in DLBCL male patients who are treated with rituximab (Cho et al., 2010). Also, in the treatment with rituximab, male patients had a worse PFS than female patients both in DLBCL and in follicular lymphoma (Riihijärvi et al., 2011).

CONCLUSIONS

The present review highlights the importance of sex differences in the epidemiology and chemotherapy of cancer. Evidence supports sex differences in efficacy and toxicity to anticancer drugs based on individual pharmacokinetics and pharmacodynamics. Data suggest that sex influences pathophysiology, clinical signs, treatment outcome and response in cancer. Sex is a crucial factor in predicting chemotherapy outcome, with implications for therapeutic efficacy and toxicity. Our review provides supporting information for appropriate chemotherapy based on sex. Based on the plethora of studies reporting potential sex differences in cancer, cancer research and therapy should be considered specifically to enhance patient outcomes. Sex difference in cancer susceptibility can be used to develop a causal hypothesis for the disease, or to define subgroups at the highest risk for preventive action. Sex plays a crucial role in improving individual pharmacogenomics and in developing personalized therapeutic medicines. Pharmacogenomic differences between the sexes might play a significant role in chemotherapy in the future. Further studies are needed to provide greater insight into sex differences in cancer and improve treatment outcomes with anticancer agents.

Acknowledgments

The present study was supported by the Duksung Women’s University Research Grant 2016.

Footnotes

CONFLICT OF INTEREST

The authors declare no conflict of interest.

REFERENCES

  1. Anderson GD. Sex and racial differences in pharmacological response: where is the evidence? Pharmacogenetics, pharmacokinetics, and pharmacodynamics. J Womens Health (Larchmt) 2005;14:19–29. doi: 10.1089/jwh.2005.14.19. [DOI] [PubMed] [Google Scholar]
  2. Arand M, Mühlbauer R, Hengstler J, Jäger E, Fuchs J, Winkler L, Oesch F. A multiplex polymerase chain reaction protocol for the simultaneous analysis of the glutathione S-transferase GSTM1 and GSTT1 polymorphisms. Anal Biochem. 1996;236:184–186. doi: 10.1006/abio.1996.0153. [DOI] [PubMed] [Google Scholar]
  3. Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global patterns and trends in colorectal cancer incidence and mortality. Gut. 2017;66:683–691. doi: 10.1136/gutjnl-2015-310912. [DOI] [PubMed] [Google Scholar]
  4. Asher G, Lotem J, Kama R, Sachs L, Shaul Y. NQO1 stabilizes p53 through a distinct pathway. Proc Natl Acad Sci USA. 2002;99:3099–3104. doi: 10.1073/pnas.052706799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Becker JB, Arnold AP, Berkley KJ, Blaustein JD, Eckel LA, Hampson E, Herman JP, Marts S, Sadee W, Steiner M, Taylor J, Young E. Strategies and methods for research on sex differences in brain and behavior. Endocrinology. 2005;146:1650–1673. doi: 10.1210/en.2004-1142. [DOI] [PubMed] [Google Scholar]
  6. Bellon SF, Coleman JH, Lippard SJ. DNA unwinding produced by site-specific intrastrand cross-links of the antitumor drug cis-diamminedichloroplatinum (II) Biochemistry. 1991;30:8026–8035. doi: 10.1021/bi00246a021. [DOI] [PubMed] [Google Scholar]
  7. Bertuccio P, Chatenoud L, Levi F, Praud D, Ferlay J, Negri E, Malvezzi M, La Vecchia C. Recent patterns in gastric cancer: a global overview. Int J Cancer. 2009;125:666–673. doi: 10.1002/ijc.24290. [DOI] [PubMed] [Google Scholar]
  8. Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC, Bargonetti J, Bartel F, Taubert H, Wuerl P, Onel K, Yip L, Hwang SJ, Strong LC, Lozano G, Levine AJ. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell. 2004;119:591–602. doi: 10.1016/j.cell.2004.11.022. [DOI] [PubMed] [Google Scholar]
  9. Bond GL, Hirshfield KM, Kirchhoff T, Alexe G, Bond EE, Robins H, Bartel F, Taubert H, Wuerl P, Hait W, Toppmeyer D, Offit K, Levine AJ. MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer Res. 2006;66:5104–5110. doi: 10.1158/0008-5472.CAN-06-0180. [DOI] [PubMed] [Google Scholar]
  10. Bolufer P, Collado M, Barragán E, Cervera J, Calasanz MJ, Colomer D, Roman-Gómez J, Sanz MA. The potential effect of gender in combination with common genetic polymorphisms of drug-metabolizing enzymes on the risk of developing acute leukemia. Haematologica. 2007;92:308–314. doi: 10.3324/haematol.10752. [DOI] [PubMed] [Google Scholar]
  11. Brahmer JR, Dahlberg SE, Gray RJ, Schiller JH, Perry MC, Sandler A, Johnson DH. Sex differences in outcome with bevacizumab therapy: analysis of patients with advanced-stage non-small cell lung cancer treated with or without bevacizumab in combination with paclitaxel and carboplatin in the Eastern Cooperative Oncology Group Trial 4599. J Thorac Oncol. 2011;6:103–108. doi: 10.1097/JTO.0b013e3181fa8efd. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Bren L. Does sex make a difference? FDA Consum. 2005;39:10–15. [PubMed] [Google Scholar]
  13. Cho HJ, Eom HS, Kim HJ, Kim IS, Lee GW, Kong SY. Glutathione-S-transferase genotypes influence the risk of chemotherapy-related toxicities and prognosis in Korean patients with diffuse large B-cell lymphoma. Cancer Genet Cytogenet. 2010;198:40–46. doi: 10.1016/j.cancergencyto.2009.12.004. [DOI] [PubMed] [Google Scholar]
  14. Crocetti E, Mallone S, Robsahm TE, Gavin A, Agius D, Ardanaz E, Lopez MC, Innos K, Minicozzi P, Borgognoni L, Pierannunzio D, Eisemann N, EUROCARE-5 Working Group Survival of patients with skin melanoma in Europe increases further: results of the EUROCARE-5 study. Eur J Cancer. 2015;51:2179–2190. doi: 10.1016/j.ejca.2015.07.039. [DOI] [PubMed] [Google Scholar]
  15. Diasio RB, Harris BE. Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet. 1989;16:215–237. doi: 10.2165/00003088-198916040-00002. [DOI] [PubMed] [Google Scholar]
  16. Do TN, Ucisik-Akkaya E, Davis CF, Morrison BA, Dorak MT. An intronic polymorphism of IRF4 gene influences gene transcription in vitro and shows a risk association with childhood acute lymphoblastic leukemia in males. Biochim Biophys Acta. 2010;1802:292–300. doi: 10.1016/j.bbadis.2009.10.015. [DOI] [PubMed] [Google Scholar]
  17. Dobbs NA, Twelves CJ, Gillies H, James CA, Harper PG, Rubens RD. Gender affects doxorubicin pharmacokinetics in patients with normal liver biochemistry. Cancer Chemother Pharmacol. 1995;36:473–476. doi: 10.1007/BF00685796. [DOI] [PubMed] [Google Scholar]
  18. Dorak MT, Karpuzoglu E. Gender differences in cancer susceptibility: an inadequately addressed issue. Front Genet. 2012;3:268. doi: 10.3389/fgene.2012.00268. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Eliyahu D, Michalovitz D, Eliyahu S, Pinhasi-Kimhi O, Oren M. Wild-type p53 can inhibit oncogene-mediated focus formation. Proc Natl Acad Sci USA. 1989;86:8763–8767. doi: 10.1073/pnas.86.22.8763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Etienne MC, Lagrange JL, Dassonville O, Fleming R, Thyss A, Renée N, Schneider M, Demard F, Milano G. Population study of dihydropyrimidine dehydrogenase in cancer patients. J Clin Oncol. 1994;12:2248–2253. doi: 10.1200/JCO.1994.12.11.2248. [DOI] [PubMed] [Google Scholar]
  21. Everson GT, McKinley C, Kern F., Jr Mechanisms of gallstone formation in women. Effects of exogenous estrogen (Premarin) and dietary cholesterol on hepatic lipid metabolism. J Clin Invest. 1991;87:237–246. doi: 10.1172/JCI114977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Fagerholm R, Hofstetter B, Tommiska J, Aaltonen K, Vrtel R, Syrjäkoski K, Kallioniemi A, Kilpivaara O, Mannermaa A, Kosma VM, Uusitupa M, Eskelinen M, Kataja V, Aittomäki K, von Smitten K, Heikkilä P, Lukas J, Holli K, Bartkova J, Blomqvist C, Bartek J, Nevanlinna H. NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer. Nat Genet. 2008;40:844–853. doi: 10.1038/ng.155. [DOI] [PubMed] [Google Scholar]
  23. Farhana L, Nangia-Makker P, Arbit E, Shango K, Sarkar S, Mahmud H, Hadden T, Yu Y, Majumdar AP. Bile acid: a potential inducer of colon cancer stem cells. Stem Cell Res Ther. 2016;7:181. doi: 10.1186/s13287-016-0439-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25:581–611. doi: 10.1210/er.2003-0027. [DOI] [PubMed] [Google Scholar]
  25. Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, Brenner H, Dicker DJ, Chimed-Orchir O, Dandona R, Dandona L, Fleming T, Forouzanfar MH, Hancock J, Hay RJ, Hunter-Merrill R, Huynh C, Hosgood HD, Johnson CO, Jonas JB, Khubchandani J, Kumar GA, Kutz M, Lan Q, Larson HJ, Liang X, Lim SS, Lopez AD, MacIntyre MF, Marczak L, Marquez N, Mokdad AH, Pinho C, Pourmalek F, Salomon JA, Sanabria JR, Sandar L, Sartorius B, Schwartz SM, Shackelford KA, Shibuya K, Stanaway J, Steiner C, Sun J, Takahashi K, Vollset SE, Vos T, Wagner JA, Wang H, Westerman R, Zeeb H, Zoeckler L, Abd-Allah F, Ahmed MB, Alabed S, Alam NK, Aldhahri SF, Alem G, Alemayohu MA, Ali R, Al-Raddadi R, Amare A, Amoako Y, Artaman A, Asayesh H, Atnafu N, Awasthi A, Saleem HB, Barac A, Bedi N, Bensenor I, Berhane A, Bernabé E, Betsu B, Binagwaho A, Boneya D, Campos-Nonato I, Castañeda-Orjula C, Catalá-López F, Chiang P, Chibueze C, Chitheer A, Choi JY, Cowie B, Damtew S, das Neves J, Dey S, Dharmaratne S, Dhillon P, Ding E, Driscoll T, Ekwueme D, Endries AY, Farvid M, Farzadfar F, Fernandes J, Fischer F, G/Hiwot TT, Gebru A, Gopalani S, Hailu A, Horino M, Horita N, Husseini A, Huybrechts I, Inoue M, Islami F, Jakovljevic M, James S, Javanbakht M, Jee SH, Kasaeian A, Kedir MS, Khader YS, Khang YH, Kim D, Leigh J, Linn S, Lunevicius R, El Razek HMA, Malekzadeh R, Malta DC, Marcenes W, Markos D, Melaku YA, Meles KG, Mendoza W, Mengiste DT, Meretoja TJ, Miller TR, Mohammad KA, Mohammadi A, Mohammed S, Moradi-Lakeh M, Nagel G, Nand D, Le Nguyen Q, Nolte S, Ogbo FA, Oladimeji KE, Oren E, Pa M, Park EK, Pereira DM, Plass D, Qorbani M, Radfar A, Rafay A, Rahman M, Rana SM, Søreide K, Satpathy M, Sawhney M, Sepanlou SG, Shaikh MA, She J, Shiue I, Shore HR, Shrime MG, So S, Soneji S, Stathopoulou V, Stroumpoulis K, Sufiyan MB, Sykes BL, Tabarés-Seisdedos R, Tadese F, Tedla BA, Tessema GA, Thakur JS, Tran BX, Ukwaja KN, Uzochukwu BSC, Vlassov VV, Weiderpass E, Wubshet Terefe M, Yebyo HG, Yimam HH, Yonemoto N, Younis MZ, Yu C, Zaidi Z, Zaki MES, Zenebe ZM, Murray CJL, Naghavi M. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study. JAMA Oncol. 2017;3:524–548. doi: 10.1001/jamaoncol.2016.5688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Frisancho AR. Triceps skin fold and upper arm muscle size norms for assessment of nutrition status. Am J Clin Nutr. 1974;27:1052–1058. doi: 10.1093/ajcn/27.8.1052. [DOI] [PubMed] [Google Scholar]
  27. Gewirtz DA. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol. 1999;57:727–741. doi: 10.1016/S0006-2952(98)00307-4. [DOI] [PubMed] [Google Scholar]
  28. Grodstein F, Newcomb PA, Stampfer MJ. Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am J Med. 1999;106:574–582. doi: 10.1016/S0002-9343(99)00063-7. [DOI] [PubMed] [Google Scholar]
  29. Harris BE, Carpenter JT, Diasio RB. Severe 5-fluorouracil toxicity secondary to dihydropyrimidine dehydrogenase deficiency. A potentially more common pharmacogenetic syndrome. Cancer. 1991;68:499–501. doi: 10.1002/1097-0142(19910801)68:3<499::AID-CNCR2820680309>3.0.CO;2-F. [DOI] [PubMed] [Google Scholar]
  30. Hayes JD, Strange RC. Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology. 2000;61:154–166. doi: 10.1159/000028396. [DOI] [PubMed] [Google Scholar]
  31. Hsu YT, Wolter KG, Youle RJ. Cytosol-to-membrane redistribution of Bax and Bcl-X(L) during apoptosis. Proc Natl Acad Sci USA. 1997;94:3668–3672. doi: 10.1073/pnas.94.8.3668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Huang RS, Kistner EO, Bleibel WK, Shukla SJ, Dolan ME. Effect of population and gender on chemotherapeutic agent-induced cytotoxicity. Mol Cancer Ther. 2007;6:31–36. doi: 10.1158/1535-7163.MCT-06-0591. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Islam MM, Iqbal U, Walther BA, Nguyen PA, Li YJ, Dubey NK, Poly TN, Masud JHB, Atique S, Syed-Abdul S. Gender-based personalized pharmacotherapy: a systematic review. Arch Gynecol Obstet. 2017;295:1305–1317. doi: 10.1007/s00404-017-4363-3. [DOI] [PubMed] [Google Scholar]
  34. Joerger M, Huitema AD, van den Bongard DH, Schellens JH, Beijnen JH. Quantitative effect of gender, age, liver function, and body size on the population pharmacokinetics of Paclitaxel in patients with solid tumors. Clin Cancer Res. 2006;12:2150–2157. doi: 10.1158/1078-0432.CCR-05-2069. [DOI] [PubMed] [Google Scholar]
  35. Jordan MA, Wilson Microtubules as a target for anticancer drugs. Nat Rev Cancer. 2004;4:253–265. doi: 10.1038/nrc1317. [DOI] [PubMed] [Google Scholar]
  36. Keitt SK, Fagan TF, Marts SA. Understanding sex differences in environmental health: a thought leaders’ roundtable. Environ Health Perspect. 2004;112:604–609. doi: 10.1289/ehp.6714. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Kim SE, Paik HY, Yoon H, Lee JE, Kim N, Sung MK. Sex- and gender-specific disparities in colorectal cancer risk. World J Gastroenterol. 2015;21:5167–5175. doi: 10.3748/wjg.v21.i17.5167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Lee ML, Chen GG, Vlantis AC, Tse GM, Leung BC, van Hasselt CA. Induction of thyroid papillary carcinoma cell proliferation by estrogen is associated with an altered expression of Bcl-xL. Cancer J. 2005;11:113–121. doi: 10.1097/00130404-200503000-00006. [DOI] [PubMed] [Google Scholar]
  39. Ley CJ, Lees B, Stevenson JC. Sex- and menopause-associated changes in body-fat distribution. Am J Clin Nutr. 1992;55:950–954. doi: 10.1093/ajcn/55.5.950. [DOI] [PubMed] [Google Scholar]
  40. Liaw CC, Wang CH, Chang HK, Liau CT, Yeh KY, Huang JS, Lin YC. Gender discrepancy observed between chemotherapy-induced emesis and hiccups. Support Care Cancer. 2001;9:435–441. doi: 10.1007/s005200000231. [DOI] [PubMed] [Google Scholar]
  41. Lipshultz SE, Colan SD, Gelber RD, Perez-Atayde AR, Sallan SE, Sanders SP. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med. 1991;324:808–815. doi: 10.1056/NEJM199103213241205. [DOI] [PubMed] [Google Scholar]
  42. Lipshultz SE, Lipsitz SR, Mone SM, Goorin AM, Sallan SE, Sanders SP, Orav EJ, Gelber RD, Colan SD. Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med. 1995;332:1738–1743. doi: 10.1056/NEJM199506293322602. [DOI] [PubMed] [Google Scholar]
  43. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3:330–338. doi: 10.1038/nrc1074. [DOI] [PubMed] [Google Scholar]
  44. Lu JF, Bruno R, Eppler S, Novotny W, Lum B, Gaudreault J. Clinical pharmacokinetics of bevacizumab in patients with solid tumors. Cancer Chemother Pharmacol. 2008;62:779–786. doi: 10.1007/s00280-007-0664-8. [DOI] [PubMed] [Google Scholar]
  45. Mader RM. The potential of gender-specific tumor pharmacology. Pharmacogenomics. 2007;8:271–274. doi: 10.2217/14622416.8.3.271. [DOI] [PubMed] [Google Scholar]
  46. Mannervik B, Danielson UH. Glutathione transferases-structure and catalytic activity. CRC Crit Rev Biochem. 1988;23:283–337. doi: 10.3109/10409238809088226. [DOI] [PubMed] [Google Scholar]
  47. McMichael AJ, Potter JD. Reproduction, endogenous and exogenous sex hormones, and colon cancer: a review and hypothesis. J Natl Cancer Inst. 1980;65:1201–1207. [PubMed] [Google Scholar]
  48. Merkatz RB, Temple R, Subel S, Feiden K, Kessler DA. Women in clinical trials of new drugs. A change in Food and Drug Administration policy. The working group on women in clinical trials. N Engl J Med. 1993;329:292–296. doi: 10.1056/NEJM199307223290429. [DOI] [PubMed] [Google Scholar]
  49. Milano G, Etienne MC, Cassuto-Viguier E, Thyss A, Santini J, Frenay M, Renee N, Schneider M, Demard F. Influence of sex and age on fluorouracil clearance. J Clin Oncol. 1992;10:1171–1175. doi: 10.1200/JCO.1992.10.7.1171. [DOI] [PubMed] [Google Scholar]
  50. Milano G, Etienne MC, Pierrefite V, Barberi-Heyob M, Deporte-Fety R, Renée N. Dihydropyrimidine dehydrogenase deficiency and fluorouracil-related toxicity. Br J Cancer. 1999;79:627–630. doi: 10.1038/sj.bjc.6690098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Mitry MA, Edwards JG. Doxorubicin induced heart failure: phenotype and molecular mechanisms. Int J Cardiol Heart Vasc. 2016;10:17–24. doi: 10.1016/j.ijcha.2015.11.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Müller C, Murawski N, Wiesen MH, Held G, Poeschel V, Zeynalova S, Wenger M, Nickenig C, Peter N, Lengfelder E, Metzner B, Rixecker T, Zwick C, Pfreundschuh M, Reiser M. The role of sex and weight on rituximab clearance and serum elimination half-life in elderly patients with DLBCL. Blood. 2012;119:3276–3284. doi: 10.1182/blood-2011-09-380949. [DOI] [PubMed] [Google Scholar]
  53. Naghavi M, Abajobir AA, Abbafati C, Abbas KM, Abd-Allah F, Abera SF, Aboyans V, Adetokunboh O, Afshin A, Agrawal A, Ahmadi A, Ahmed MB, Aichour AN, Aichour MTE, Aichour I, Aiyar S, Alahdab F, Al-Aly Z, Alam K, Alam N, Alam T, Alene KA, Al-Eyadhy A, Ali SD, Alizadeh-Navaei R, Alkaabi JM, Alkerwi A, Alla F, Allebeck P, Allen C, Al-Raddadi R, Alsharif U, Altirkawi KA, Alvis-Guzman N, Amare AT, Amini E, Ammar W, Amoako YA, Anber N, Andersen HH, Andrei CL, Androudi S, Ansari H, Antonio CAT, Anwari P, Ärnlöv J, Arora M, Artaman A, Aryal K K, Asayesh H, Asgedom S W, Atey T M, Avila-Burgos L, Avokpaho E F G, Awasthi A, Babalola T K, Bacha U, Balakrishnan K, Barac A, Barboza M A, Barker-Collo S L, Barquera S, Barregard L, Barrero L H, Baune B T, Bedi N, Beghi E, Béjot Y, Bekele B B, Bell M L, Bennett J R, Bensenor I M, Berhane A, Bernabé E, Betsu B D, Beuran M, Bhatt S, Biadgilign S, Bienhoff K, Bikbov B, Bisanzio D, Bourne R R A, Breitborde N J K, Bulto L N B, Bumgarner B R, Butt Z A, Cahuana-Hurtado L, Cameron E, Campuzano J C, Car J, Cárdenas R, Carrero J J, Carter A, Casey D C, Castañeda-Orjuela C A, Catalá-López F, Charlson F J, Chibueze C E, Chimed-Ochir O, Chisumpa V H, Chitheer A A, Christopher D J, Ciobanu L G, Cirillo M, Cohen A J, Colombara D, Cooper C, Cowie B C, Criqui M H, Dandona L, Dandona R, Dargan P I, das Neves J, Davitoiu D V, Davletov K, de Courten B, Defo B K, Degenhardt L, Deiparine S, Deribe K, Deribew A, Dey S, Dicker D, Ding E L, Djalalinia S, Do H P, Doku D T, Douwes-Schultz D, Driscoll T R, Dubey M, Duncan B B, Echko M, El-Khatib Z Z, Ellingsen C L, Enayati A, Ermakov S P, Erskine H E, Eskandarieh S, Esteghamati A, Estep K, Farinha C S E S, Faro A, Farzadfar F, Feigin V L, Fereshtehnejad S M, Fernandes J C, Ferrari A J, Feyissa T R, Filip I, Finegold S, Fischer F, Fitzmaurice C, Flaxman AD, Foigt N, Frank T, Fraser M, Fullman N, Fürst T, Furtado JM, Gakidou E, Garcia-Basteiro AL, Gebre T, Gebregergs GB, Gebrehiwot TT, Gebremichael DY, Geleijnse JM, Genova-Maleras R, Gesesew HA, Gething PW, Gillum RF, Giref AZ, Giroud M, Giussani G, Godwin WW, Gold AL, Goldberg EM, Gona PN, Gopalani SV, Gouda HN, Goulart AC, Griswold M, Gupta R, Gupta T, Gupta V, Gupta PC, Haagsma JA, Hafezi-Nejad N, Hailu AD, Hailu GB, Hamadeh RR, Hambisa MT, Hamidi S, Hammami M, Hancock J, Handal AJ, Hankey GJ, Hao Y, Harb HL, Hareri HA, Hassanvand MS, Havmoeller R, Hay SI, He F, Hedayati MT, Henry NJ, Heredia-Pi IB, Herteliu C, Hoek HW, Horino M, Horita N, Hosgood HD, Hostiuc S, Hotez PJ, Hoy DG, Huynh C, Iburg KM, Ikeda C, Ileanu BV, Irenso AA, Irvine CMS, Islam SMS, Jacobsen KH, Jahanmehr N, Jakovljevic MB, Javanbakht M, Jayaraman SP, Jeemon P, Jha V, John D, Johnson CO, Johnson SC, Jonas JB, Jürisson M, Kabir Z, Kadel R, Kahsay A, Kamal R, Karch A, Karimi SM, Karimkhani C, Kasaeian A, Kassaw NA, Kassebaum NJ, Katikireddi SV, Kawakami N, Keiyoro PN, Kemmer L, Kesavachandran CN, Khader YS, Khan EA, Khang YH, Khoja ATA, Khosravi MH, Khosravi A, Khubchandani J, Kiadaliri AA, Kieling C, Kievlan D, Kim YJ, Kim D, Kimokoti RW, Kinfu Y, Kissoon N, Kivimaki M, Knudsen AK, Kopec JA, Kosen S, Koul PA, Koyanagi A, Kulikoff XR, Kumar GA, Kumar P, Kutz M, Kyu HH, Lal DK, Lalloo R, Lambert TLN, Lan Q, Lansingh VC, Larsson A, Lee PH, Leigh J, Leung J, Levi M, Li Y, Li Kappe D, Liang X, Liben ML, Lim SS, Liu PY, Liu A, Liu Y, Lodha R, Logroscino G, Lorkowski S, Lotufo PA, Lozano R, Lucas TCD, Ma S, Macarayan ERK, Maddison ER, Magdy Abd El Razek M, Majdan M, Majdzadeh R, Majeed A, Malekzadeh R, Malhotra R, Malta DC, Manguerra H, Manyazewal T, Mapoma CC, Marczak LB, Markos D, Martinez-Raga J, Martins-Melo FR, Martopullo I, McAlinden C, McGaughey M, McGrath JJ, Mehata S, Meier T, Meles KG, Memiah P, Memish ZA, Mengesha MM, Mengistu DT, Menota BG, Mensah GA, Meretoja TJ, Meretoja A, Millear A, Miller TR, Minnig S, Mirarefin M, Mirrakhimov EM, Misganaw A, Mishra SR, Mohamed IA, Mohammad KA, Mohammadi A, Mohammed S, Mokdad AH, Mola GLD, Mollenkopf SK, Molokhia M, Monasta L, Montañez JC, Montico M, Mooney MD, Moradi-Lakeh M, Moraga P, Morawska L, Morozoff C, Morrison SD, Mountjoy-Venning C, Mruts KB, Muller K, Murthy GVS, Musa KI, Nachega JB, Naheed A, Naldi L, Nangia V, Nascimento BR, Nasher JT, Natarajan G, Negoi I, Ngunjiri JW, Nguyen CT, Nguyen QL, Nguyen TH, Nguyen G, Nguyen M, Nichols E, Ningrum DNA, Nong VM, Noubiap JJN, Ogbo FA, Oh IH, Okoro A, Olagunju AT, Olsen HE, Olusanya BO, Olusanya JO, Ong K, Opio JN, Oren E, Ortiz A, Osman M, Ota E, Pa M, Pacella RE, Pakhale S, Pana A, Panda BK, Panda-Jonas S, Papachristou C, Park EK, Patten SB, Patton GC, Paudel D, Paulson K, Pereira DM, Perez-Ruiz F, Perico N, Pervaiz A, Petzold M, Phillips MR, Pigott DM, Pinho C, Plass D, Pletcher MA, Polinder S, Postma MJ, Pourmalek F, Purcell C, Qorbani M, Quintanilla BPA, Radfar A, Rafay A, Rahimi-Movaghar V, Rahman MHU, Rahman M, Rai RK, Ranabhat CL, Rankin Z, Rao PC, Rath GK, Rawaf S, Ray SE, Rehm J, Reiner RC, Reitsma MB, Remuzzi G, Rezaei S, Rezai MS, Rokni MB, Ronfani L, Roshandel G, Roth GA, Rothenbacher D, Ruhago GM, Sa R, Saadat S, Sachdev PS, Sadat N, Safdarian M, Safi S, Safiri S, Sagar R, Sahathevan R, Salama J, Salamati P, Salomon JA, Samy AM, Sanabria JR, Sanchez-Niño MD, Santomauro D, Santos IS, Santric Milicevic MM, Sartorius B, Satpathy M, Schmidt MI, Schneider IJC, Schulhofer-Wohl S, Schutte AE, Schwebel DC, Schwendicke F, Sepanlou SG, Servan-Mori EE, Shackelford KA, Shahraz S, Shaikh MA, Shamsipour M, Shamsizadeh M, Sharma J, Sharma R, She J, Sheikhbahaei S, Shey M, Shi P, Shields C, Shigematsu M, Shiri R, Shirude S, Shiue I, Shoman H, Shrime MG, Sigfusdottir ID, Silpakit N, Silva JP, Singh JA, Singh A, Skiadaresi E, Sligar A, Smith DL, Smith A, Smith M, Sobaih BHA, Soneji S, Sorensen RJD, Soriano JB, Sreeramareddy CT, Srinivasan V, Stanaway JD, Stathopoulou V, Steel N, Stein DJ, Steiner C, Steinke S, Stokes MA, Strong M, Strub B, Subart M, Sufiyan MB, Sunguya BF, Sur PJ, Swaminathan S, Sykes BL, Tabarés-Seisdedos R, Tadakamadla SK, Takahashi K, Takala JS, Talongwa RT, Tarawneh MR, Tavakkoli M, Taveira N, Tegegne TK, Tehrani-Banihashemi A, Temsah MH, Terkawi AS, Thakur JS, Thamsuwan O, Thankappan KR, Thomas KE, Thompson AH, Thomson AJ, Thrift AG, Tobe-Gai R, Topor-Madry R, Torre A, Tortajada M, Towbin JA, Tran BX, Troeger C, Truelsen T, Tsoi D, Tuzcu EM, Tyrovolas S, Ukwaja KN, Undurraga EA, Updike R, Uthman OA, Uzochukwu BSC, van Boven JFM, Vasankari T, Venketasubramanian N, Violante FS, Vlassov VV, Vollset SE, Vos T, Wakayo T, Wallin MT, Wang YP, Weiderpass E, Weintraub RG, Weiss DJ, Werdecker A, Westerman R, Whetter B, Whiteford HA, Wijeratne T, Wiysonge CS, Woldeyes BG, Wolfe CDA, Woodbrook R, Workicho A, Xavier D, Xiao Q, Xu G, Yaghoubi M, Yakob B, Yano Y, Yaseri M, Yimam HH, Yonemoto N, Yoon SJ, Yotebieng M, Younis MZ, Zaidi Z, Zaki MES, Zegeye EA, Zenebe ZM, Zerfu TA, Zhang AL, Zhang X, Zipkin B, Zodpey S, Lopez AD, Murray CJL. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980–2016 a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390:1151–1210. doi: 10.1016/S0140-6736(17)32152-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Rademaker M. Do women have more adverse drug reactions? Am J Clin Dermatol. 2001;2:349–351. doi: 10.2165/00128071-200102060-00001. [DOI] [PubMed] [Google Scholar]
  55. Raftogianis RB, Wood TC, Otterness DM, Van Loon JA, Weinshilboum RM. Phenol sulfotransferase pharmacogenetics in humans: association of common SULT1A1 alleles with TS PST phenotype. Biochem Biophys Res Commun. 1997;239:298–304. doi: 10.1006/bbrc.1997.7466. [DOI] [PubMed] [Google Scholar]
  56. Riihijärvi S, Taskinen M, Jerkeman M, Leppä S. Male gender is an adverse prognostic factor in B-cell lymphoma patients treated with immunochemotherapy. Eur J Haematol. 2011;86:124–128. doi: 10.1111/j.1600-0609.2010.01541.x. [DOI] [PubMed] [Google Scholar]
  57. Rivankar S. An overview of doxorubicin formulations in cancer therapy. J Cancer Res Ther. 2014;10:853–858. doi: 10.4103/0973-1482.139267. [DOI] [PubMed] [Google Scholar]
  58. Rodvold KA, Rushing DA, Tewksbury DA. Doxorubicin clearance in the obese. J Clin Oncol. 1988;6:1321–1327. doi: 10.1200/JCO.1988.6.8.1321. [DOI] [PubMed] [Google Scholar]
  59. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–2550. doi: 10.1056/NEJMoa061884. [DOI] [PubMed] [Google Scholar]
  60. Santi DV, McHenry CS, Sommer H. Mechanism of interaction of thymidylate synthetase with 5-fluorodeoxyuridylate. Biochemistry. 1974;13:471–481. doi: 10.1021/bi00700a012. [DOI] [PubMed] [Google Scholar]
  61. Schiff PB, Horwitz SB. Taxol stabilizes microtubules in mouse fibroblast cells. Proc Natl Acad Sci USA. 1980;77:1561–1565. doi: 10.1073/pnas.77.3.1561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Schmetzer O, Flörcken A. Sex differences in the drug therapy for oncologic diseases. In: Regitz-Zagrosek V, editor. Sex and Gender Differences in Pharmacology. Springer; Germany: 2012. pp. 411–442. [DOI] [PubMed] [Google Scholar]
  63. Schuetz EG, Furuya KN, Schuetz JD. Interindividual variation in expression of P-glycoprotein in normal human liver and secondary hepatic neoplasms. J Pharmacol Exp Ther. 1995;275:1011–1018. [PubMed] [Google Scholar]
  64. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30. doi: 10.3322/caac.21332. [DOI] [PubMed] [Google Scholar]
  65. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30. doi: 10.3322/caac.21387. [DOI] [PubMed] [Google Scholar]
  66. Sloan JA, Goldberg RM, Sargent DJ, Vargas-Chanes D, Nair S, Cha SS, Novotny PJ, Poon MA, O’Connell MJ, Loprinzi CL. Women experience greater toxicity with fluorouracil-based chemotherapy for colorectal cancer. J Clin Oncol. 2002;20:1491–1498. doi: 10.1200/JCO.2002.20.6.1491. [DOI] [PubMed] [Google Scholar]
  67. Stein BN, Petrelli NJ, Douglass HO, Driscoll DL, Arcangeli G, Meropol NJ. Age and sex are independent predictors of 5-fluorouracil toxicity. Analysis of a large scale phase III trial. Cancer. 1995;75:11–17. doi: 10.1002/1097-0142(19950101)75:1<11::AID-CNCR2820750104>3.0.CO;2-N. [DOI] [PubMed] [Google Scholar]
  68. Torre LA, Siegel RL, Ward EM, Jemal A. Global cancer incidence and mortality rates and trends--an update. Cancer Epidemiol Biomarkers Prev. 2016;25:16–27. doi: 10.1158/1055-9965.EPI-15-0578. [DOI] [PubMed] [Google Scholar]
  69. Tran C, Knowles SR, Liu BA, Shear NH. Gender differences in adverse drug reactions. J Clin Pharmacol. 1998;38:1003–1009. doi: 10.1177/009127009803801103. [DOI] [PubMed] [Google Scholar]
  70. Traver RD, Horikoshi T, Danenberg KD, Stadlbauer TH, Danenberg PV, Ross D, Gibson NW. NAD(P)H:quinone oxidoreductase gene expression in human colon carcinoma cells: characterization of a mutation which modulates DT-diaphorase activity and mitomycin sensitivity. Cancer Res. 1992;52:797–802. [PubMed] [Google Scholar]
  71. van Asperen J, van Tellingen O, Tijssen F, Schinkel AH, Beijnen JH. Increased accumulation of doxorubicin and doxorubicinol in cardiac tissue of mice lacking mdr1a P-glycoprotein. Br J Cancer. 1999;79:108–113. doi: 10.1038/sj.bjc.6690019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Wang J, Huang Y. Pharmacogenomics of sex difference in chemotherapeutic toxicity. Curr Drug Discov Technol. 2007;4:59–68. doi: 10.2174/157016307781115485. [DOI] [PubMed] [Google Scholar]
  73. Wasternack C. Degradation of pyrimidines and pyrimidine analogs--pathways and mutual influences. Pharmacol Ther. 1980;8:629–651. doi: 10.1016/0163-7258(80)90079-0. [DOI] [PubMed] [Google Scholar]
  74. Wei Q, Cheng L, Amos CI, Wang LE, Guo Z, Hong WK, Spitz MR. Repair of tobacco carcinogen-induced DNA adducts and lung cancer risk: a molecular epidemiologic study. J Natl Cancer Inst. 2000;92:1764–1772. doi: 10.1093/jnci/92.21.1764. [DOI] [PubMed] [Google Scholar]
  75. Wongtawatchai T, Agthong S, Kaewsema A, Chentanez V. Sex-related differences in cisplatin-induced neuropathy in rats. J Med Assoc Thai. 2009;92:1485–1491. [PubMed] [Google Scholar]
  76. Yamamoto H, Sekine I, Yamada K, Nokihara H, Yamamoto N, Kunitoh H, Ohe Y, Tamura T. Gender differences in treatment outcomes among patients with non-small cell lung cancer given a combination of carboplatin and paclitaxel. Oncology. 2008;75:169–174. doi: 10.1159/000159268. [DOI] [PubMed] [Google Scholar]
  77. Yoshioka A, Tanaka S, Hiraoka O, Koyama Y, Hirota Y, Ayusawa D, Seno T, Garrett C, Wataya Y. Deoxyribonucleoside triphosphate imbalance. 5-Fluorodeoxyuridine-induced DNA double strand breaks in mouse FM3A cells and the mechanism of cell death. J Biol Chem. 1987;262:8235–8241. [PubMed] [Google Scholar]
  78. Zheng L, Wang Y, Schabath MB, Grossman HB, Wu X. Sulfotransferase 1A1 (SULT1A1) polymorphism and bladder cancer risk: a case-control study. Cancer Lett. 2003;202:61–69. doi: 10.1016/j.canlet.2003.08.007. [DOI] [PubMed] [Google Scholar]
  79. Zucker I, Beery AK. Males still dominate animal studies. Nature. 2010;465:690. doi: 10.1038/465690a. [DOI] [PubMed] [Google Scholar]

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