Pharmacogenetics of toxicity of 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients

Abstract

The differences in patients’ response to the same medication, toxicity included, are one of the major problems in breast cancer treatment. Chemotherapy toxicity makes a significant clinical problem due to decreased quality of life, prolongation of treatment and reinforcement of negative emotions associated with therapy.In this study we evaluated the genetic and clinical risk factors of FAC chemotherapy-related toxicities in the group of 324 breast cancer patients. Selected genes and their polymorphisms were involved in FAC drugs transport (ABCB1, ABCC2, ABCG2,SLC22A16), metabolism (ALDH3A1, CBR1, CYP1B1, CYP2C19, DPYD, GSTM1, GSTP1, GSTT1, MTHFR,TYMS), DNA damage recognition, repair and cell cycle control (ATM, ERCC1, ERCC2, TP53, XRCC1).The multifactorial risk models that combine genetic risk modifiers and clinical characteristics were constructed for 12 toxic symptoms. The majority of toxicities was dependent on the modifications in components of more than one pathway of FAC drugs, while the impact level of clinical factors was comparable to the genetic ones. For the carriers of multiple high risk factors the chance of developing given symptom was significantly elevated which proved the factor-dosage effect. We found the strongest associations between concurrent presence of clinical factors - overall and recurrent anemia, nephrotoxicity and early nausea and genetic polymorphisms in genes responsible for DNA repair, drugs metabolism and transport pathways. These results indicate the possibility of selection of the patients with expected high tolerance to FAC treatment and consequently with high chance of chemotherapy completion without the dose reduction, treatment delays and decline in the quality of life.

Genetic 3′UTR variations and clinical factors significantly contribute to survival prediction and clinical response in breast cancer patients

“…Our results are consistent with the results of Lal et al 2007, that SNPs in SLC22A16 are associated with shorter OS and PFS in Asian breast cancer patients 51 . Furthermore, earlier studies confirmed the association of SNPs within SLC22A16 with toxic side effects in chemotherapy in breast cancer patients 36,50,52 . Additionally, overexpression of SLC22A16 in cancer cells is associated with the increasing influx of doxorubicin into cell and correlates with increased sensitivity to cytotoxic effects of this drug 53 .…”

“…Stepwise regression made possible to obtain data on independent prognostic factors (p ≤ 0.05) of FAC chemotherapy. Cumulative analyzes enabled us to estimate the risk of non-response to the therapy for two or more independent factors, as described previously 36 .…”

Sterically Stabilised Polymeric Mesoporous Silica Nanoparticles Improve Doxorubicin Efficiency: Tailored Cancer Therapy

“…The pore size diameter, calculated according to Barrett, Joyner, and Halenda (BJH) was 9.8 nm (98 Å) (from desorption branch), with a cumulative surface area of 710. 36 Post-grafting was utilised to functionalise the surface of the MSNs, by protonating their outer surface and increasing their hydrophilicity [46]. This contributed to the enlarged hydrodynamic sizes from NTA (Table 1).…”

“…These cytostatic or cytotoxic compounds usually have low bioavailability and are thus administered at high dosages or for prolonged dosing intervals, leading to systemic side effects at non-specific sites [19,20].Doxorubicin (DOX) remains one of the most efficient anthracycline drugs available and is used in the treatment of diverse cancers, including breast, cervical, bone, gastric and leukaemia [21][22][23]. Despite its popularity, its low solubility [24][25][26], coupled with increased dosing frequencies [27][28][29] has resulted in many associated side effects, including cardiotoxicity [30][31][32], myelosuppression [33,34], induced vomiting with nausea [35,36], and alopecia [18,37]. Critical evaluation of these detrimental side-effects that become more pronounced as dosing durations increase has concluded that both chronic and acute DOX-induced cytotoxicity can be largely reduced with improved and targeted administration routes [21,38].…”

Synergistic Effect of Resveratrol with 5-Fluorouracil in Chemotherapy of Induced Oral Squamous Cell Carcinoma

“…In most cases, its treatment involves chemotherapy (1) . However, the drug toxicity and/or tumor cell resistance are obstacles to the choice of chemotherapy (2) . Scientific studies proved that combining chemotherapy with specific antioxidants, at defined dosages can improve drug efficacy and/or may reduce the severity of side effects (3,4) .…”