Drugs In Cancer Patients Research Articles

New Insight into 2-Methoxyestradiol- a Possible Physiological Link between Neurodegeneration and Cancer Cell Death.

The pathways leading to development of neurodegenerative disease and cancer cell death may overlap. Interestingly, the main neurodegeneration-causing factors have been suggested to play a pivotal role in the regulation of tumor growth. Another common component in neurodegenerations and cancer is nitro-oxidative stress. Depending on the environmental conditions, the nitro-oxidative stress may lead to cancerogenesis or cancer cell death. On the other side, it may also result in a variety of neurodegenerative diseases. Based on the literature data, we suggest that 2-methoxyestradiol may be considered as a physiological link between development of neurodegenerations and cancer cell death. 2-methoxyestradiol is a physiological compound, a metabolite of 17β-estradiol. Interestingly, 2-methoxyestradiol, branded as Panzem, is also considered as a potent anticancer agent, currently investigated in several clinical trials. The review aims on making closer the facts concerning anticancer and plausible neurotoxic activities of 2-methoxyestradiol, which may suggest adverse neurological long-term effects of the drug in cancer patients.

Pharmacokinetic variations in cancer patients with liver dysfunction: applications and challenges of pharmacometabolomics.

In cancer patients, pharmacokinetic variations between individuals and within individuals due to impairments in organs' function and other reasons such as genetic polymorphisms represent a major problem in disease management, which can result in unpredictable toxicity and variable antineoplastic effects. Addressing pharmacokinetic variations in cancer patients with liver dysfunction and their implications on anticancer and analgesic drugs, in addition to the use of advanced analytical techniques such as metabolomics and pharmacometabolomics, to monitor altered kinetic and discover metabolic biomarkers during therapeutic intervention will help in understanding and reducing pharmacokinetic variations of drugs in cancer patients as a step forward towards personalised medicine. Reviewing published literature addressing and/or related to complications resulting from altered pharmacokinetics (PKs) in cancer patients with liver dysfunction, anticancer and analgesic drugs, evaluating recent advances of pharmacokinetic detection using metabolomics/pharmacometabolomics and the challenges that are currently facing these techniques. The current situation presents a pressing need to reduce pharmacokinetic variations of drugs in cancer patients. Although most of the omics technologies are not entirely focussed on the study of pharmacokinetic variations and some studies are met with uncertainty, the use of pharmacometabolomics combined with other omics technology such as pharmacogenomics can provide clues to personalised cancer treatments by providing useful information about the cancer patient's response to medical interventions via identification of patients' dependent variables, understanding of correlations between individuals and population PKs, and therapy outcomes to achieve optimum therapeutic effects with minimum toxicity. We also propose an approach for PKs' evaluation using pharmacometabolomics.

A single treatment of Selenate, a repositioning drug, specifically sensitizes P-gp-overexpressing resistant cancer cells

We investigated possible conditions or drugs that might enhance the sensitivity of anti-mitotic drug-resistant cancer cells. We particularly focused on identifying mechanisms or drugs that could sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells. Our approach utilized repositioning drugs, which are already used in clinics, because once their sensitization mechanisms on resistant cancer cells are known, they would be readily applied without further toxicity studies. Selenium-derived drugs such as selenate, selenite, selenomethionine (SeMet), methyl-selenocysteine (MSC), and methaneselenic acid (MSA) have been shown to have anti-cancer properties clinically. The type of selenium-derived drug that can specifically sensitize P-gp-overexpressing resistant KBV20C cancer cells was investigated for further application in the clinical settings. We recently reported five selenium-derived drugs that could sensitize both resistant KBV20C and KB parent sensitive cancer cells without P-gp inhibition. Among these five drugs, our study highlights the unprecedented finding of the selective sensitization ability of selenate against P-gp-overexpressed resistant KBV20C cells. Detailed analysis indicates that selenate is a resistant cancer cell-specific sensitizing drug that increases apoptosis via G2-phase cell cycle arrest. These results may help improve chemotherapeutic treatments based on selenium-derived drugs for cancer patients who develop resistance to anti-mitotic drugs.

Abstract 4422: TTT-28, a newly synthesized thiazole-valine peptide, antagonizes multidrug resistance by inhibiting the efflux activity of the ABCB1 transporter

Abstract Cancer cells often exhibit either intrinsic or acquired resistance to chemotherapy through a phenomenon known as multidrug resistance (MDR). Different mechanisms contribute to the development of MDR, preeminent among them being the accelerated drug efflux mediated by overexpression of ATP-binding cassette (ABC) transporters. Currently, it has been found that some small molecule tyrosine kinase inhibitors (TKIs), such as motesanib, linsitinib, masitinib and nilotinib, were able to modulate the activity of ABC transporters. Thus, the aim of this study was to determine whether TTT-28, a newly synthesized thiazole-valine peptide, could reverse ABCB1-mediated MDR. The results showed that TTT-28 significantly sensitized both ABCB1-transfected and drug-selected cell lines overexpressing this transporter to its substrate anticancer drugs. Using calcein-AM efflux assay, we identified TTT-28 (IC50 = 1.0 μM) carrying 3,4,5-trimethoxybenzoyl and 2-aminobenzophenone groups, respectively, at the amino and carboxyl termini of the monothiazole zwitterion. TTT-28 significantly increased the accumulation of [3H]-paclitaxel in ABCB1 overexpressing cells by blocking the efflux function of ABCB1 transporter. Furthermore, TTT-28 inhibited the photolabeling of ABCB1 with [125I]-iodoarylazidoprazosin with IC50 = 0.75 μM and stimulated the basal ATP hydrolysis of ABCB1 in a concentration-dependent manner (EC50 ATPase = 0.027 μM). Consistent with these findings, biochemical and docking studies showed site-1 to be the preferable binding site for TTT-28 within the drug-binding pocket of human ABCB1. Therefore, we report that TTT-28 antagonizes MDR by inhibiting the efflux activity of the ABCB1 transporter. These findings reveal high clinical values for the co-administration of TTT-28 and ABCB1 substrate chemotherapeutic drugs in cancer patients that overexpress ABCB1 and stimulate further research on circumventing the ABCB1-mediated MDR in cancers. Citation Format: Yi-Jun Wang, Nagaraju Anreddy, Bhargav A. Patel, Eduardo E. Chufan, Satyakam Singh, Guan-Nan Zhang, Yun-Kai Zhang, Anna Maria Barbuti, Suresh V. Ambudkar, Tanaji T. Talele, Zhe-Sheng Chen. TTT-28, a newly synthesized thiazole-valine peptide, antagonizes multidrug resistance by inhibiting the efflux activity of the ABCB1 transporter. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4422. doi:10.1158/1538-7445.AM2015-4422

Potential and real 'antineoplastic' and metabolic effect of metformin in diabetic and nondiabetic postmenopausal females.

The goal of this study was to determine if the single nucleotide polymorphisms marking potential sensitivity to metformin (MF) correlate with hormone-metabolic status as well as with actual response to MF in postmenopausal cancer patients with or without Type 2 diabetes mellitus and in diabetics without cancer. The carriage of ten different SNPs was evaluated in all patients by PCR, and hormone-metabolic status was estimated by anthropometry, ELISA and enzyme colorimetric assays. The response to daily 1-1.7 g of MF was studied based on hormone-metabolic parameters and indirect end points (endometrium thickness, mammographic breast density). The changes in evaluated 'antineoplastic' and metabolic response marker values were seen in 33.3 and 61.8% of the cases, respectively. Several genetic markers were found that showed an inclination to less frequent 'antineoplastic' or more frequent metabolic response to MF which may be helpful in further studies of this drug in cancer patients.

Redox-active and redox-silent compounds: synergistic therapeutics in cancer.

Tumours exhibit higher basal levels of reactive oxygen species (ROS) and altered redox environment compared to normal cells. Excessive level of ROS can be toxic to these cells, thus they become more vulnerable to damage by further ROS insults induced by pharmacological agents. However, the upregulation of antioxidant capacity in adaptation to intrinsic oxidative stress in cancer cells can confer drug resistance. Therefore, abrogation of such drug-resistant mechanisms by redox modulation could have significant therapeutic implications. Many redox-modulating agents have been developed. The redox-active system epitomised by ascorbate-driven quinone redox cycling, and the group of redox-silent vitamin E analogues represented by α-tocopheryl succinate have been shown to induce selective cancer cell death in different types of cancer. These compounds synergistically act by destabilising organelles like mitochondria, unleashing their apoptogenic potential, which results in efficient death of malignant cells and suppression of tumour growth. Consistent with this notion, clinical trials that aim to examine the therapeutic performance of novel redox-modulating drugs in cancer patients are currently under way.

Incidence and risk of severe infections associated with anti-epidermal growth factor receptor monoclonal antibodies in cancer patients: a systematic review and meta-analysis.

BackgroundAnti-epidermal growth factor receptor (EGFR)-monoclonal antibodies (MoAbs) have been widely used in a variety of malignancies. Severe infections (≥grade 3) are potentially life-threatening adverse events with these drugs. However, the contribution of anti-EGFR MoAbs to infections is still unknown. We performed this meta-analysis to determine the overall incidence and risk of severe infections in cancer patients treated with these drugs.MethodsThe databases of PubMed and abstracts presented at oncology conferences and published in the proceedings were searched for relevant studies from January 2000 to May 2014. Summary incidences, relative risks (RRs) and 95% confidence intervals (CIs) were calculated by using either random effects or fixed effect models according to the heterogeneity of included studies.ResultsA total of 14,066 patients from 26 randomized controlled trials (RCTs) were included. The use of anti-EGFR-MoAbs significantly increased the risk of developing severe infections (RR 1.34, 95%CI: 1.10 to 1.62, P = 0.003) in cancer patients, but not for fatal infections (RR 1.62, 95%CI: 0.81 to 3.26, P = 0.18). Meta-regression indicated the infections might possibly occur early in the treatment with anti-EGFR MoAbs. On sub-group analysis, the risk of severe infections significantly varied with tumor type (P = 0.001). When stratified by specific anti-EGFR MoAbs, a significantly increased risk of infections with cetuximab was observed (P <0.001), but not for panitumumab (P = 0.98). Additionally, the use of anti-EGFR MoAbs significantly increased the risk of severe infections when used in conjunction with cisplatin (RR 1.48, 95%CI 1.22 to 1.79, P <0.001) or irinotecan (RR 1.53, 95%CI 1.12 to 2.10, P = 0.008). When stratified by specific infectious events, anti-EGFR-MoAbs significantly increased the risk of developing severe sepsis (RR 4.30, 95%CI: 1.80 to 10.27; P = 0.001).ConclusionsAnti-EGFR MoAbs treatment significantly increases the risk of developing severe infectious events in cancer patients. The risk may vary with tumor types. Clinicians should be aware of the risks of severe infections with the administration of these drugs in cancer patients.

Bevacizumab increases the risk of severe congestive heart failure in cancer patients: an up-to-date meta-analysis with a focus on different subgroups.

Congestive heart failure (CHF) risk with bevacizumab in breast cancer has been previously investigated in a meta-analysis, but its incidence and the risk of CHF in other tumor types remain unclear. Thus, we performed this meta-analysis to gather current data and evaluate the risk of CHF with bevacizumab in cancer patients, with a focus on different subgroups. The databases of PubMed and abstracts presented at the American Society of Clinical Oncology up to 31 December 2013 were searched for relevant articles. Statistical analyses were conducted to calculate the summary incidence, relative risk (RR), and 95 % confidence intervals (CIs) by using either random-effects or fixed-effect models according to the heterogeneity of included studies. A total of 16,962 patients from 19 RCTs were included. The use of bevacizumab significantly increased the risk of developing high-grade CHF in cancer patients (RR 1.98, 95 % CI 1.30-3.02, p = 0.002), but not for all-grade CHF (RR 1.14, 95 % CI 0.87-1.49, p = 0.33). Risk might vary with bevacizumab dose and tumor types. RRs for patients receiving bevacizumab at 5 and 2.5 mg/kg/week were 2.25 (95 % CI 1.43-3.56) and 1.00 (95 % CI 0.33-3.05), respectively. High risks were observed in patients with breast cancer (RR 2.43, 95 % CI 1.48-3.98), renal cell cancer (RR 3.66, 95 % CI 0.41-33.01), and glioblastoma (RR 4.90, 95 % CI 0.24-102.39). Additionally, bevacizumab in combination with taxanes significantly increased the risk of high-grade CHF (RR 2.15, 95 % CI 1.09-4.25, p = 0.027). Bevacizumab treatment significantly increases the risk of developing high-grade CHF in cancer patients. The risk may vary with bevacizumab dose and tumor types. Clinicians should be aware of the risks of CHF with the administration of this drug in cancer patients.

Effectiveness of combinations of Ayurvedic drugs in alleviating drug toxicity and improving quality of life of cancer patients treated with chemotherapy.

This study was conducted to assess the effectiveness of combinations of Ayurvedic drugs in alleviating the toxicity of chemotherapy and improving the quality of life of cancer patients. The following was the research question: Can Ayurvedic drugs be used to alleviate the side effects of chemotherapy and improve the quality of life of cancer patients? Random patients with malignancies of different tissues, grades, and stages were divided into two groups according to their treatment modality. Group 1 consisted of 15 patients treated with six cycles of chemotherapy alone and who did not receive any Ayurvedic drugs (control group). Group 2 consisted of patients (divided into three arms) who received Ayurvedic drugs during chemotherapy and after chemotherapy. Nineteen patients in arm 1 received the Ayurvedic drugs Mauktikyukta Kamdudha (MKD) and Mauktikyukta Praval Panchamruta (MPP) along with a full course of chemotherapy. Fifteen patients in arm 2 received the same Ayurvedic treatment, but the treatment was started after completing the sixth cycle of chemotherapy. Eighteen patients in arm 3 received the Suvarnabhasmadi formulation (SBD) in addition to MKD and MPP after completing the sixth cycle of chemotherapy. Treatment was given for 16 weeks in all three arms. Patients from both groups were observed for a period of 6 months. The assessment criteria depended on Common Toxicity Criteria (CTC designed by NIH and NCI): haemogram; weight; physical examination including Quality of Life Questionnaire (QLQ designed by the European Organization of Research and Treatment of Cancer (EORTC)) for functional, symptom and global scores; and Karnofsky score for assessment of general well-being and activities of daily life. ECOG (Eastern Cooperation Oncology Group) score was also additionally included for assessment of symptoms. From amongst the symptomatic criteria, there was significant improvement in all the three arms compared with the control group in nausea, loss of appetite, constipation, and fatigue. There was significant improvement in the Karnofsky score and global score of the QLQ, which in fact incorporate symptomatic criteria, general condition, functional ability and disease-related symptoms. These significant differences were observed in group 2 (arms 1, 2, 3) in comparison with group 1 (control), in spite of the fact that in arms 2 and 3, the Ayurvedic treatment was started after completion of chemotherapy. The haemogram did not show a significant difference between the control and the three arms of group 2. Adjunct treatment with herbo-mineral and metallic Ayurvedic drugs appears to have a significant effect on reducing the toxic side effects of chemotherapy drugs in cancer patients. Our preliminary data suggests that Ayurvedic treatment should be given simultaneously from the beginning of chemotherapy to have the desired effect. However, there is a need to extend this work by conducting a well-planned two-armed study on cancer patients with defined cancer sites with selected Ayurvedic drug combinations, and observing the patients for a longer period of time to confirm the effectiveness of Ayurvedic drugs in reducing the side effects of chemotherapy.

New orally active anticoagulant agents for the prevention and treatment of venous thromboembolism in cancer patients

Patients with cancer have a 6–7-fold higher risk of venous thromboembolism (VTE) as compared with non-cancer patients. Effective and safe anticoagulation for the prevention and treatment of VTE is the cornerstone of the management of patients with cancer, aiming to decrease morbidity and mortality and to improve quality of life. Unfractionated heparin, low molecular weight heparins, fondaparinux and vitamin K antagonists (VKAs) are used in the prevention and treatment of VTE in cancer patients. Heparins and fondaparinux are administered subcutaneously. VKAs are orally active, but they have a narrow therapeutic window, numerous food and drug interactions, and treatment requires regular laboratory monitoring and dose adjustment. These limitations among others have important negative impact on the quality of life of patients and decrease adherence to the treatment. New orally active anticoagulant (NOAC) agents are specific inhibitors of activated factor Xa (FXa) (rivaroxaban and apixaban) or thrombin (dabigatran). It is expected that NOACs will improve antithrombotic treatment. Cancer patients are a particular group that could benefit from treatment with NOACs. However, NOACs present some significant interactions with drugs frequently used in cancer patients, which might influence their pharmacokinetics, compromising their efficacy and safety. In the present review, we analyzed the available data from the subgroups of patients with active cancer who were included in Phase III clinical trials that assessed the efficacy and safety of NOACs in the prevention and treatment of VTE. The data from the Phase III trials in prophylaxis of VTE by rivaroxaban or apixaban highlight that these two agents, although belonging to the same pharmacological group (direct inhibitors of factor Xa), have substantially different profiles of efficacy and safety, especially in hospitalized acutely ill medical patients with active cancer. A limited number of patients with VTE and active cancer were included in the Phase III trials (EINSTEIN, AMPLIFY, and RE-COVER) which evaluated the efficacy and safety of NOACs in the acute phase and secondary prevention of VTE. Although, from a conceptual point of view, NOACs could be an attractive alternative for the treatment of VTE in cancer patients, the available data do not support this option. In addition, due to the elimination of the NOACs by the liver and renal pathway as well as because of their pharmacological interactions with drugs which are frequently used in cancer patients, an eventual use of these drugs in cancer patients should be extremely cautious and be restricted only to patients presenting with contraindications for low molecular weight heparins, fondaparinux, or VKAs. The analysis of the available data presented in this review reinforces the request for the design of new Phase III clinical trials for the assessment of the efficacy and safety of NOACs in specific populations of patients with cancer.

Bevacizumab increases the risk of gastrointestinal perforation in cancer patients: a meta-analysis with a focus on different subgroups.

The aim of this meta-analysis was to gather current data and evaluate not only the risk of gastrointestinal (GI) perforation with bevacizumab, but also the potential risk factors for this adverse event. We carried out a literature search in PubMed for randomized controlled trials (RCTs) reported from January 2000 to December 2013. Summary incidence, relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of the included studies. A total of 26,833 patients from 33 RCTs were included in the meta-analysis. Bevacizumab-containing therapy significantly increased the risk of developing all-grade (RR 3.35, 95% CI 2.35-4.79, P < 0.001) and fatal GI perforation (RR 3.08, 95%CI: 1.04-9.08, P = 0.042). On subgroup analysis, no significant risk differences were found based on bevacizumab dosage, treatment duration, treatment line, type of clinical trial and median age. When stratified by tumor types, a significantly increased risk of GI perforation with bevacizumab was observed in colorectal cancer (RR 2.84, 95% CI 1.43-5.61, P = 0.003), gynecologic cancer (RR 3.37, 95% CI 1.71-6.62, P < 0.001) and prostate cancer (RR 6.01, 95% CI 1.78-20.28, P = 0.004). Additionally, the use of bevacizumab significantly increased the risk of GI perforation when used in conjunction with taxanes (RR 3.09, 95% CI 1.92-4.96, P < 0.001) or oxaliplatin (RR 2.85, 95% CI 1.07-7.57, P = 0.036). Bevacizumab treatment is associated with a significantly increased risk of developing GI perforation, and clinicians should be aware of the risks of GI perforation with the administration of this drug in cancer patients.

Strategy of Daiichi Sankyo Discovery Research in Oncology

We would like to introduce Daiichi Sankyo's approach to developing cancer targeted medicines with special reference to the drug discovery strategy, global discovery activities and external research collaboration leading to generation of innovative drugs for cancer patients. We are developing 14 clinical projects for cancer treatment and three of them have been previously approved. These are mostly targeted for growth and survival signals of cancer cells. To overcome the drug resistance mechanism derived from the heterogeneous nature of cancer, we are developing selective inhibitors in three major clusters of signal pathways which may allow future rational combinations of oncology products. In addition to the main research facility in Japan, research sites in the EU and the USA provide us with different technical expertise and diversified ideas of drug discovery. To access novel drug targets, we are facilitating research collaboration with leading academia and successful cancer research scientists. In conclusion, we intend to focus more on developing innovative personalized medicines for better treatment of cancer.

“To Serve and Protect”: Enzyme Inhibitors as Radiopeptide Escorts Promote Tumor Targeting

Radiolabeled octreotide analogs are most successfully being applied today in clinical cancer imaging and treatment. Propagation of this paradigm to other radiopeptide families has been greatly hampered by the inherent poor metabolic stability of systemically administered peptide analogs. We hypothesized that the in vivo coadministration of specific enzyme inhibitors would improve peptide bioavailability and hence tumor uptake. Through single coinjection of the neutral endopeptidase inhibitor phosphoramidon (PA), we were able to provoke remarkable rises in the percentages of circulating intact somatostatin, gastrin, and bombesin radiopeptides in mouse models, resulting in a remarkable increase in uptake in tumor xenografts in mice. The peptide conjugates [DOTA-Ala(1)]SS14 (DOTA-Ala-Gly-c[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys]-OH), PanSB1 (DOTA-PEG2-dTyr-Gln-Trp-Ala-Val-βAla-His-Phe-Nle-NH2), and DOTA-MG11 (DOTA-dGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) were labeled with (111)In by 20 min of heating at an acidic pH. Metabolic stability was studied with high-performance liquid chromatography analysis of blood samples collected 5 min after the injection of the test radiopeptide alone or with PA into mice. Biodistribution was studied after injection of each (111)In-labeled radiopeptide alone or after coinjection of PA in tumor-bearing severe combined immunodeficient (SCID) mice. The amount of intact [(111)In-DOTA-Ala(1)]SS14 detected in the mouse circulation at 5 min after the injection of PA increased impressively-from less than 2% to 86%-whereas the uptake in AR4-2J xenografts rose from less than 1 percentage injected dose per gram of tissue (%ID/g) to 14 %ID/g at 4 h after injection. Likewise, the coadministration of PA resulted in a marked increase in the amount of circulating intact (111)In-PanSB1-from 12% to 80%-at 5 min after injection, and radioligand uptake in human PC-3 xenografts in SCID mice escalated from less than 4 %ID/g to greater than 21 %ID/g at 4 h after injection. In a similar manner, the coadministration of PA resulted in an equally impressive increase in intact [(111)In-DOTA]MG11 levels in the mouse bloodstream-from less than 5% to 70%-at 5 min after injection, leading to a remarkable increase in radiotracer uptake-from 2 %ID/g to greater than 15 %ID/g-in both AR4-2J tumors and A431(CCKR+) tumors (i.e., tumors induced by A431 cells transfected to stably express the human cholecystokinin subtype 2 receptor) in mice at 4 h after injection. This effect was well visualized by SPECT/CT imaging of AR4-2J tumor-bearing mice at 4 h after injection. The results of this study clearly demonstrate that the coadministration of key enzyme inhibitors can effectively prolong the survival of radiolabeled peptides in the circulation, securing their safe transit to the target. This strategy clearly provoked an unprecedented increase in radiolabel accumulation in tumor xenografts in mice; this increase might translate into higher diagnostic sensitivity or improved therapeutic efficacy of radiopeptide drugs in cancer patients. Hence, our findings provide exciting new opportunities for the application of biodegradable (radio)peptide drugs of either natural or synthetic origin as well as for the rationale design of analogs that are stable in vivo.

An HPLC-UV method for the simultaneous quantification of vemurafenib and erlotinib in plasma from cancer patients

Vemurafenib and erlotinib are two oral kinase inhibitors approved for the treatment of metastatic melanoma and advanced non-small cell lung cancer, respectively. In contrast with erlotinib, the single published method for analysis of vemurafenib in human plasma is based on mass spectrometry. The purpose of the present study was to develop an HPLC-UV method to simultaneously quantify these two drugs in plasma. Following liquid-liquid extraction, vemurafenib, erlotinib and sorafenib (internal standard) were separated isocratically on a C8 Xterra(®) MS using a mobile phase of glycine buffer (pH 9.0, 100mM)/acetonitrile (45:55, v/v). Samples were eluted at a flow rate of 0.9mL/min throughout the 12-min run. Dual UV wavelength mode was used, with vemurafenib and sorafenib monitored at 249nm, and erlotinib at 331nm. The calibration was linear in the range 1.25-100mg/L and 50-4000μg/L for vemurafenib and erlotinib, respectively. Inter- and intra-day precision was less than 6.7% and 6.6% for vemurafenib and erlotinib, respectively. This analytical method was successfully applied to assess the steady state plasma exposure of these drugs in cancer patients. This accurate method can be used in routine clinical practice to monitor vemurafenib or erlotinib concentrations in plasma from cancer patients.

Role of aldo-keto reductases and other doxorubicin pharmacokinetic genes in doxorubicin resistance, DNA binding, and subcellular localization

BackgroundSince proteins involved in chemotherapy drug pharmacokinetics and pharmacodynamics have a strong impact on the uptake, metabolism, and efflux of such drugs, they likely play critical roles in resistance to chemotherapy drugs in cancer patients.MethodsTo investigate this hypothesis, we conducted a whole genome microarray study to identify difference in the expression of genes between isogenic doxorubicin-sensitive and doxorubicin-resistant MCF-7 breast tumour cells. We then assessed the degree of over-representation of doxorubicin pharmacokinetic and pharmacodynamic genes in the dataset of doxorubicin resistance genes.ResultsOf 27,958 Entrez genes on the array, 7.4 per cent or 2,063 genes were differentially expressed by ≥ 2-fold between wildtype and doxorubicin-resistant cells. The false discovery rate was set at 0.01 and the minimum p value for significance for any gene within the “hit list” was 0.01. Seventeen and 43 per cent of doxorubicin pharmacokinetic genes were over-represented in the hit list, depending upon whether the gene name was identical or within the same gene family, respectively. The most over-represented genes were within the 1C and 1B families of aldo-keto reductases (AKRs), which convert doxorubicin to doxorubicinol. Other genes convert doxorubicin to other metabolites or affect the influx, efflux, or cytotoxicity of the drug. In further support of the role of AKRs in doxorubicin resistance, we observed that, in comparison to doxorubicin, doxorubincol exhibited dramatically reduced cytotoxicity, reduced DNA-binding activity, and strong localization to extra nuclear lysosomes. Pharmacologic inhibition of the above AKRs in doxorubicin-resistant cells increased cellular doxorubicin levels, restored doxorubicin cytotoxicity and re-established doxorubicin localization to the nucleus. The properties of doxorubicinol were unaffected.ConclusionsThese findings demonstrate the utility of using curated pharmacokinetic and pharmacodynamic knowledge bases to identify highly relevant genes associated with doxorubicin resistance. The induction of one or more of these genes was found to be correlated with changes in the drug’s properties, while inhibiting one specific class of these genes (the AKRs) increased cellular doxorubicin content and restored drug DNA binding, cytotoxicity, and subcellular localization.

Prescription patterns for psychotropic drugs in cancer patients; a large population study in the Netherlands

Psychotropic drugs are commonly prescribed for various psychological complaints in cancer patients. We aim to examine the prescription pattern in cancer patients of three common psychotropic drugs: benzodiazepine, antidepressant and antipsychotic. This is a retrospective case-control study. Data were extracted from the Agis Health Database. This insurance database contains the healthcare consumption of 1.3 million inhabitants of the Netherlands. We analyzed the use of psychotropics in cancer patients and an equally sized randomly selected control group of noncancer patients from 2006 to 2008. Odds ratio (OR) were adjusted for age, gender, immigrant status, neighborhood socio-economic status, and premorbid medical condition. Additionally, the numbers of new user in the 3 months after cancer was diagnosed and in the 3 months before death were compared. A total of 113 887 cancer patients and 121 395 control subjects were included. Cancer patients were significantly more often prescribed psychotropic drugs (adjusted OR: benzodiazepines = 1.70, CI = 1.67-1.74; antidepressants = 1.38, CI = 1.34-1.42; and antipsychotics = 1.70, CI = 1.62-1.77). Lower socio-economic status, immigrant, and premorbid chronic medical conditions were significantly associated with higher risk of psychotropic use. Odds for a new prescription for all three psychotropic drugs were significantly less in the first 3 months after cancer diagnosis than the 3 months before death (benzodiazepine, OR = 0.673, CI = 0.647-0.705; antidepressant, OR = 0.592, CI = 0.544-0.644; antipsychotic, OR = 0.177, CI = 0.165-0.190) CONCLUSIONS: Psychotropic drug prescription is common in cancer patients, starts soon after diagnosis, and increases in the terminal stage. Prescription rates were significantly higher in patients from lower socio-economic group, immigrants, or with premorbid chronic medical condition.

Tyrosine kinase inhibitors as modulators of ABC transporter-mediated drug resistance

Tyrosine kinases (TKs) are involved in key signaling events/pathways that regulate cancer cell proliferation, apoptosis, angiogenesis and metastasis. Deregulated activity of TKs has been implicated in several types of cancers. In recent years, tyrosine kinase inhibitors (TKIs) have been developed to inhibit specific kinases whose constitutive activity results in specific cancer types. These TKIs have been found to demonstrate effective anticancer activity and some of them have been approved by the Food and Drug Administration for clinical use or are in clinical trials. However, these targeted therapeutic agents are also transported by ATP-binding cassette (ABC) transporters, resulting in altered pharmacokinetics or development of resistance to these drugs in cancer patients. This review covers the recent findings on the interactions of clinically important TKIs with ABC drug transporters. Future research efforts in the development of novel TKIs with specific targets, seeking improved activity, should consider these underlying causes of resistance to TKIs in cancer cells.

IFN-γ producing T cells contribute to the increase of myeloid derived suppressor cells in tumor-bearing mice after cyclophosphamide treatment

It has been reported that treatment with cyclophosphamide (CTX) as a chemotherapeutic drug in cancer patients or tumor-bearing mice can result in an increase in the proportion of myeloid derived suppressor cells (MDSCs) in blood and lymphoid organs. Here we sought to clarify the possible mechanism of this unwanted increase in proportion of MDSCs in tumor-bearing mice after CTX treatment. We found that both CD4+ T cells and CD8+ T cells underwent an expansion and activation before the increase of MDSCs in the early period of CTX treatment in 4T1 breast tumor-bearing mice. The proportion of MDSCs in nude mice lacking T cells after CTX therapy was comparable to that in nude mice without CTX treatment. T cell transfer to 4T1-bearing nude mice enhanced the proportion of MDSCs in tumor-bearing mice after CTX therapy. The co-culture of MDSCs and T cells in vitro also showed that CD4+ T cells and CD8+ T cells could facilitate the expansion and survival of MDSCs, and this effect was mediated by IFN-γ released by T cells. These results gave an explanation of the unwanted consequence resulted from CTX treatment in tumor-bearing mice. It also provided some insights into the strategies for eliminating the bad side of CTX treatment and to make it more effective in cancer therapy.

Randomized dose-finding studies: how many dose levels should be used?

These days, people live longer. A fact generally accredited to higher standards of living, improved self-awareness of a healthy life-style and also, importantly, better healthcare. For example, life expectancy in the USA has increased by more than 30 years in the last century, 25 years of this gain being attributible to public health benefits [1]. There is an enormous amount of medicine available for patients, ranging from cough medicine to complex chemotherapy drugs for cancer patients. The number of products, ‘distinctive medicines, described by brand or generic name, or both’ [2], listed in the physicians’ compendia in 1981 were 2100 in the UK and 6000 in the USA [3]. Currently, the pharmaceutical industry in the EU, Japan and the USA follow the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines [101] to conduct tests on medicines in preclinical trials and clinical trials before they can be granted a license by regulatory authorities. In preclinical trials, a new compound is tested on animals (in vivo) or cells (in vitro). Its toxic responses are monitored along with pharmacological aspects: pharmaco kinetics – drug concentrations in the body (cell), and pharmacodynamics – drug reactions in the body (cell), targeting certain molecules or receptors and the potentially efficacious response of the drug. Once the compound has been proven safe and has potential efficacy, it will be administered into humans to test the safety and efficacy further. Phase I clinical trials are used to establish the safety of the drug when it is first administered into humans. An identified safe dose from preclinical studies is scaled for human subjects, either by body weight or body surface areas [4]. This will form the starting dose (×) for a Phase I trial. A fixed dose range will be used. Usually it is based on a doubling scale (×, 2×, ...) or a modified Fibonacci sequence (×, 2×, 3.3×, 4.95×, ...) [5]. Each dose of this fixed range is to be tested for its safety. In cancer trials a typical study design is a parallel group, randomized and conducted on a small number of subjects, for example, 20–80. Subjects are randomly allocated into two groups: one is the treatment group (to receive the new active compound) and the other one is the control group (either to receive a placebo or an existing compound). Dose-escalation procedures either follow a predefined rule or are based on clinicians’ judgment. An example of a predefined rule is the ‘3 + 3’ up-and-down rule [6]: each treatment group contains three subjects. If no toxicity is observed within three patients, then the next group of subjects will get the next higher dose. If one out of three patients had toxicity, then the same dose will be repeated for the next group. If more than two out of three patients had toxicity, then the trial will

Multiple Loci Modulate Opioid Therapy Response for Cancer Pain

Patients treated with opioid drugs for cancer pain experience different relief responses, raising the possibility that genetic factors play a role in opioid therapy outcome. In this study, we tested the hypothesis that genetic variations may control individual response to opioid drugs in cancer patients. We tested 1 million single-nucleotide polymorphisms (SNP) in European cancer patients, selected in a first series, for extremely poor (pain relief ≤40%; n = 145) or good (pain relief ≥90%; n = 293) responses to opioid therapy using a DNA-pooling approach. Candidate SNPs identified by SNP-array were genotyped in individual samples constituting DNA pools as well as in a second series of 570 patients. Association analysis in 1,008 cancer patients identified eight SNPs significantly associated with pain relief at a statistical threshold of P < 1.0 × 10⁻³, with rs12948783, upstream of the RHBDF2 gene, showing the best statistical association (P = 8.1 × 10⁻⁹). Functional annotation analysis of SNP-tagged genes suggested the involvement of genes acting on processes of the neurologic system. Our results indicate that the identified SNP panel can modulate the response of cancer patients to opioid therapy and may provide a new tool for personalized therapy of cancer pain.