Quercetin in Cancer Treatment, Alone or in Combination with Conventional Therapeutics?

Cancer is a problem of global importance, since the incidence is increasing worldwide and therapeutic options are generally limited. Thus, it becomes imperative to find new therapeutic targets as well as new molecules with therapeutic potential for tumors. Flavonoids are polyphenolic compounds that may be potential therapeutic agents. Several studies have shown that these compounds have a higher anticancer potential. Among the flavonoids in the human diet, quercetin is one of the most important. In the last decades, several anticancer properties of quercetin have been described, such as cell signaling, pro-apoptotic, anti-proliferative and anti-oxidant effects, growth suppression. In fact, it is now well known that quercetin has diverse biological effects, inhibiting multiple enzymes involved in cell proliferation, as well as, in signal transduction pathways. On the other hand, there are also studies reporting potential synergistic effects when combined quercetin with chemotherapeutic agents or radiotherapy. In fact, several studies which aim to explore the anticancer potential of these combined treatments have already been published, the majority with promising results. Actually it is well known that quercetin can act on the chemosensitization and radiosensitization but also as chemoprotective and radioprotective, protecting normal cells of the side effects that results from chemotherapy and radiotherapy, which obviously provides notable advantages in their use in anticancer treatment. Thus, all these data indicate that quercetin may have a key role in anticancer treatment. In this context, this review is focused on the relationship between flavonoids and cancer, with special emphasis on the role of quercetin.

Release of copper complexes from a nanostructured sol–gel titania for cancer treatment

Copper complexes containing inorganic ligands were loaded on a functionalized titania (F-TiO2) to obtain drug delivery systems. The as-received copper complexes and those released from titania were tested as toxic agents on different cancer cell lines. The sol–gel method was used for the synthesis and surface functionalization of the titania, as well as for loading the copper complexes, all in a single step. The resultant Cu/F-TiO2 materials were characterized by several techniques. An “in vitro” releasing test was developed using an aqueous medium. Different concentrations (15.6–1000 µg mL−1) of each copper complex, those loaded on titania (Cu/F-TiO2), functionalized titania, and cis-Pt as a reference material, were incubated on RG2, C6, U373, and B16 cancer cell lines for 24 h. The morphology of functionalized titania and the different Cu/F-TiO2 materials obtained consists of aggregated nanoparticles, which generate mesopores. The amorphous phase (in dominant proportion) and the anatase phase were the structures identified through the X-ray diffraction profiles. These results agree with high-resolution transmission electron microscopy. Theoretical studies indicate that the copper compounds were released by a Fickian diffusion mechanism. It was found that independently of the copper complex and also the cell line used, low concentrations of each copper compound were sufficient to kill almost 100 % of cancer cells. When the cancer cells were treated with increasing concentrations of the Cu/F-TiO2 materials the number of survival cells decreased. Both copper complexes alone as well as those loaded on TiO2 had higher toxic effect than cis-Pt.

Challenges and opportunities for siRNA-based cancer treatment

As one of the life-threatening diseases involving multi-step genetic and epigenetic disorders, cancer has long been a dynamic research area for siRNA-based therapy as half of the current siRNA-based clinical trials are involved in oncology. However, despite consistent enthusiasm in the academic world, siRNA-based cancer treatment still faces obstacles and difficulties in clinical development. In this article, we discuss key challenges facing siRNA-based cancer treatment revealed from recent clinical and preclinical studies, including chemical modification, tumour penetration, endosomal escape, target selection and off-target effects. In addition, opportunities and avenues for translating siRNA technology from bench to oncologic clinics are explored.

Tamoxifen metabolism in breast cancer treatment: Taking the focus off the CYP2D6 gene

Tamoxifen (TAM) has been widely used to treat estrogen receptor (ER)-positive breast cancer, and has led to reduction of 50% in the annual recurrence rate and 30% in breast cancer mortality after 5 years of treatment.1 The prodrug TAM is a selective ER modulator that antagonizes ERs in cancer cells. However, compared with its two active metabolites 4-hydroxy-TAM (4-OH-TAM) and endoxifen, it is a relatively weak antiestrogen.

Busca de novos alvos terapêuticos no tratamento de câncer de pulmão utilizando ferramentas de biologia de sistemas

A quimioterapia e uma das formas de tratamentos para o câncer, cujo processo e pela aplicação de medicamentos que alteram a síntese de DNA, interrompendo a divisão celular. No caso do câncer de pulmão, a difículdade está no fato de que as células cancerígenas criam quimiorresistência após um determinado período de tempo. Se o indivíduo desenvolver o câncer de pulmão novamente, deverá ser aplicado outro quimioterápico no paciente, e assim por diante. Nos tratamentos atuais são utilizados combinações de drogas para contornar o problema da quimiorresistência. Este trabalho utilizou a biologia de sistemas para encontrar novos alvos protéicos para auxiliar no desenvolvimento de novos quimioterápicos para o tratamento do câncer de pulmão. Foi construída uma rede baseada nos alvos protéicos já conhecidos. A rede foi expandida com o intuito de buscar quais são as proteínas que interagem com os alvos protéicos á conhecidos. Após a expansão, foram utilizadas análises de centralidades para evidenciar as proteínas mais importantes na rede, e correlacionamos com informação de expressão gênica para verificar se as proteínas mais importantes do ponto de vista topológico estão diferencialmente sub ou super expressas. A análise de centralidade junto a mostra dos dados de expressão gênica convergiu para um bom resultado, foi possível evidenciar algumas proteínas que podem ser utilizadas como novos alvos quimioterápicos

The cost-effectiveness of total laparoscopic hysterectomy compared to total abdominal hysterectomy for the treatment of early stage endometrial cancer

Objective To summarise how costs and health benefits will change with the adoption of total laparoscopic hysterectomy compared to total abdominal hysterectomy for the treatment of early stage endometrial cancer. Design Cost-effectiveness modelling using the information from a randomised controlled trial. Participants Two hypothetical modelled cohorts of 1000 individuals undergoing total laparoscopic hysterectomy and total abdominal hysterectomy. Outcome measures Surgery costs; hospital bed days used; total healthcare costs; quality-adjusted life years; and net monetary benefits. Results For 1000 individuals receiving total laparoscopic hysterectomy surgery, the costs were $509 575 higher, 3548 hospital fewer bed days were used and total health services costs were reduced by $3 746 221. There were 39.13 more quality-adjusted life years for a 5 year period following surgery. Conclusions The adoption of total laparoscopic hysterectomy is almost certainly a good decision for health services policy makers. There is 100% probability that it will be cost saving to health services, a 86.8% probability that it will increase health benefits and a 99.5% chance that it returns net monetary benefits greater than zero.

Target acquired: Progress and promise of targeted therapeutics in the treatment of prostate cancer

Cancer is fundamentally a genomic disease caused by mutations or rearrangements in the DNA or epigenetic machinery of a patient. An emerging field in cancer treatment targets key aberrations arising from the mutational landscape of an individual patient’s disease rather than employing a cancer-wide cytotoxic therapy approach. In prostate cancer in particular, where there is an observed variation in response to standard treatments between patients with disease of a similar pathological stage and grade, mutationdirected treatment may grow to be a viable tool for clinicians to tailor more effective treatments. This review will describe a number of mutations across multiple forms of cancer that have been successfully antagonised by targeted therapeutics including their identification, the development of targeted compounds to combat them and the development of resistance to these therapies. This review will continue to examine these same mutations in the treatment and management of prostate cancer; the prevalence of targetable mutations in prostate cancer, recent clinical trials of targeted-agents and the potential or limitations for their use.

Genetically Engineered Oncolytic Adenoviruses for the Treatment of Kidney and Breast Cancer

Metastatic kidney and breast cancer are devastating diseases currently lacking efficient treatment options. One promising developmental approach in cancer treatment are oncolytic adenoviruses, which have demonstrated excellent safety in many clinical trials. However, antitumor efficacy needs to be improved in order to make oncolytic viruses a viable treatment alternative. To be able to follow oncolytic virus replication in vivo, we set up a non-invasive imaging system based on coinjection of a replication deficient luciferase expressing virus and a replication competent virus. The system was validated in vitro and in vivo and used in other projects of the thesis. In another study we showed that capsid modifications on adenoviruses result in enhanced gene transfer and increased oncolytic effect on renal cancer cells in vitro. Moreover, capsid modified oncolytic adenoviruses demonstrated significantly improved antitumor efficacy in murine kidney cancer models. To transcriptionally target kidney cancer tissue we evaluated two hypoxia response elements for their usability as tissue specific promoters using a novel dual luciferase imaging system. Based on the results of the promoter evaluation and the studies on capsid modifications, we constructed a transcriptionally and transductionally targeted oncolytic adenovirus armed with an antiangiogenic transgene for enhanced renal cell cancer specificity and improved antitumor efficacy. This virus exhibited kidney cancer specific replication and significantly improved antitumor effect in a murine model of intraperitoneal disseminated renal cell cancer. Cancer stem cells are thought to be resistant to conventional cancer drugs and might play an important role in breast cancer relapse and the formation of metastasis. Therefore, we examined if capsid modified oncolytic adenoviruses are able to kill these cells proposed to be breast cancer initiating. Efficient oncolytic effect and significant antitumor efficacy on tumors established with breast cancer initiating cells was observed, suggesting that oncolytic adenoviruses might be able to prevent breast cancer relapse and could be used in the treatment of metastatic disease. In conclusion, the results presented in this thesis suggest that genetically engineered oncolytic adenoviruses have great potential in the treatment of metastatic kidney and breast cancer.

Immediate Breast Reconstructions in the Treatment of Breast Cancer

Breast cancer is the most common form of potentially fatal cancer in women in the Western world. Better understanding of the breast cancer disease process together with developments in treatments have led to improved survival and reduced risk of recurrence, significantly influencing the acceptance of breast reconstructions as part of breast cancer treatment. Skin-sparing mastectomy followed by immediate breast reconstruction has proved superior to other forms of breast reconstruction in terms of aesthetic outcome. However, due to the relatively recent introduction of skin-sparing mastectomy concerns on the surgical and oncological safety of the operation persist. The aim of the present study is to evaluate the surgical and oncological safety of skin-sparing mastectomy and immediate breast reconstruction in a consecutive patient series with ensuing follow-up. Subsequent aims of the study are to examine possibilities of reducing surgical complications of the operation and to assess the feasibility of sentinel node biopsy together with immediate breast reconstruction. The study population comprises a consecutive series of patients having undergone skin-sparing mastectomy followed by immediate breast reconstruction at the Helsinki University Central Hospital between 1992 and 2006. In Study I, the hospital records of 207 patients, operated between 1992 and 2001, were analyzed for surgical complications and recurrences of breast cancer during follow-up. In Study II, 60 consecutive patients were randomized into either conventional diathermy or radiofrequency coagulation groups to examine possibilities of reducing skin-flap complications. Study III consists of 62 consecutive breast cancer patients evaluated for the feasibility of sentinel node biopsy simultaneously with immediate breast reconstruction. In Study IV, hospital records were analyzed to examine local recurrence of breast cancer in a consecutive series of 146 patients with Stage I or II disease. Post-operative complications in Study I included native skin-flap necrosis (10.1%), hematoma (10.1%), anastomose thrombosis (5.3%), infection (3.4%), hernia (2.6%) and loss of one microvascular flap (0.7%). The Stage I and II patients in Study IV had a local recurrence rate of 2.7%, an isolated regional lymph node recurrence rate of 2.1% and a systemic recurrence rate of 2.7%, during a mean follow-up time of 51 months. The Stage III patients in study I had a locoregional recurrence rate of 31.3% during follow-up. Radiofrequency coagulation in Study II did not decrease skin-flap complications when compared with conventional diathermy. An increased skin-flap complication rate in Study II was associated with smoking and the type of skin incision used. In Study III, eleven patients had tumor positive sentinel nodes, nine of which were detected intraoperatively. Skin-sparing mastectomy followed by immediate breast reconstruction is a safe procedure both surgically and oncologically, especially for early stage breast cancer. Tennis racket type incision is associated with an increased skin-flap complication rate. Sentinel node biopsy with intraoperative assessment of sentinel node metastases is feasible in patients undergoing immediate breast reconstruction.

Breast cancer mortality in neighbouring European countries with different level of breast screening but similar access to treatment: An analysis of WHO mortality database

Objective: To compare trends in breast cancer mortality within three pairs of neighbouring European countries in relation to implementation of screening. Design: Retrospective trend analysis.
Setting: Three country pairs (Northern Ireland (United Kingdom) v Republic of Ireland, the Netherlands v Belgium and Flanders (Belgian region south of the Netherlands), and Sweden v Norway).
Data sources: WHO mortality database on cause of death and data sources on mammography screening, cancer treatment, and risk factors for breast cancer mortality.
Main outcome measures: Changes in breast cancer mortality calculated from linear regressions of log transformed, age adjusted death rates. Joinpoint analysis was used to identify the year when trends in mortality for all ages began to change.
Results: From 1989 to 2006, deaths from breast cancer decreased by 29% in Northern Ireland and by 26% in the Republic of Ireland; by 25% in the Netherlands and by 20% in Belgium and 25% in Flanders; and by 16% in Sweden and by 24% in Norway. The time trend and year of downward inflexion were similar between Northern Ireland and the Republic of Ireland and between the Netherlands and Flanders. In Sweden, mortality rates have steadily decreased since 1972, with no downward inflexion until 2006. Countries of each pair had similar healthcare services and prevalence of risk factors for breast cancer mortality but differing implementation of mammography screening, with a gap of about 10-15 years.
Conclusions: The contrast between the time differences in implementation of mammography screening and the similarity in reductions in mortality between the country pairs suggest that screening did not play a direct part in the reductions in breast cancer mortality.

Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial

Background: When cure is impossible, cancer treatment should focus on both length and quality of life. Maximisation of time without toxic effects could be one effective strategy to achieve both of these goals. The COIN trial assessed preplanned treatment holidays in advanced colorectal cancer to achieve this aim. Methods: COIN was a randomised controlled trial in patients with previously untreated advanced colorectal cancer. Patients received either continuous oxaliplatin and fluoropyrimidine combination (arm A), continuous chemotherapy plus cetuximab (arm B), or intermittent (arm C) chemotherapy. In arms A and B, treatment continued until development of progressive disease, cumulative toxic effects, or the patient chose to stop. In arm C, patients who had not progressed at their 12-week scan started a chemotherapy-free interval until evidence of disease progression, when the same treatment was restarted. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and B is described in a companion paper. Here, we compare arms A and C, with the primary objective of establishing whether overall survival on intermittent therapy was non-inferior to that on continuous therapy, with a predefined non-inferiority boundary of 1·162. Intention-to-treat (ITT) and per-protocol analyses were done. This trial is registered, ISRCTN27286448. Findings: 1630 patients were randomly assigned to treatment groups (815 to continuous and 815 to intermittent therapy). Median survival in the ITT population (n=815 in both groups) was 15·8 months (IQR 9·4—26·1) in arm A and 14·4 months (8·0—24·7) in arm C (hazard ratio [HR] 1·084, 80% CI 1·008—1·165). In the per-protocol population (arm A, n=467; arm C, n=511), median survival was 19·6 months (13·0—28·1) in arm A and 18·0 months (12·1—29·3) in arm C (HR 1·087, 0·986—1·198). The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary. Preplanned subgroup analyses in the per-protocol population showed that a raised baseline platelet count, defined as 400 000 per µL or higher (271 [28%] of 978 patients), was associated with poor survival with intermittent chemotherapy: the HR for comparison of arm C and arm A in patients with a normal platelet count was 0·96 (95% CI 0·80—1·15, p=0·66), versus 1·54 (1·17—2·03, p=0·0018) in patients with a raised platelet count (p=0·0027 for interaction). In the per-protocol population, more patients on continuous than on intermittent treatment had grade 3 or worse haematological toxic effects (72 [15%] vs 60 [12%]), whereas nausea and vomiting were more common on intermittent treatment (11 [2%] vs 43 [8%]). Grade 3 or worse peripheral neuropathy (126 [27%] vs 25 [5%]) and hand—foot syndrome (21 [4%] vs 15 [3%]) were more frequent on continuous than on intermittent treatment. Interpretation: Although this trial did not show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in terms of overall survival, chemotherapy-free intervals remain a treatment option for some patients with advanced colorectal cancer, offering reduced time on chemotherapy, reduced cumulative toxic effects, and improved quality of life. Subgroup analyses suggest that patients with normal baseline platelet counts could gain the benefits of intermittent chemotherapy without detriment in survival, whereas those with raised baseline platelet counts have impaired survival and quality of life with intermittent chemotherapy and should not receive a treatment break.

Factors affecting treatment decision making for women with breast cancer

This study examined the factors affecting treatment decision making for young women with early stage breast cancer. Thirty women, aged 35 to 52 years, were presented information about two equally effective chemotherapy treatments following surgery for breast cancer using an educational instrument called a "decision board." Although equally effective, the treatments differ with regards to side effects and treatment schedule. The purpose of this research was to investigate what factors affect the decision-making process. Following administration of the decision board, women were given a take-home version to review and asked to return one to two weeks later with a decision, at which time they completed a questionnaire. theoretical framework for this study was constructed from the literature on self-directed learning and critical thinking. The Overall, the factors rated most important to the treatment decision were related to quality of life, side effects, and length of treatment. Five factors were found to be rated significantly different by the women who chose one treatment versus the other in terms of importance to their decision. These were side effects in general, vomiting, hair loss, family role, and the number of trips to the cancer centre required for treatment.Implications and recommendations for patient education, research, and practice evolved from the findings of this study.

Treatment non-adherence in teenage and young adult patients with cancer

Adhering to treatment can be a significant issue for many patients diagnosed with chronic health conditions and this has been reported to be greater during the adolescent years. However, little is known about treatment adherence in teenage and young adult (TYA) patients with cancer. To increase awareness of the adherence challenges faced by these patients, we have reviewed the published work. The available evidence suggests that a substantial proportion of TYA patients with cancer do have difficulties, with reports that up to 63% of patients do not adhere to their treatment regimens. However, with inconsistent findings across studies, the true extent of non-adherence for these young patients is still unclear. Furthermore, it is apparent that there are many components of the cancer treatment regimen that have yet to be assessed in relation to patient adherence. Factors that have been shown to affect treatment adherence in TYA patients include patient emotional functioning (depression and self-esteem), patient health beliefs (perceived illness severity and vulnerability), and family environment (parental support and parent–child concordance). Strategies that foster greater patient adherence are also identified. These strategies are multifactorial, targeting not only the patient, but the health professional, family, and treatment regimen. This review highlights the lack of interventional studies addressing treatment adherence in TYA patients with cancer, with only one such intervention being identified: a video game intervention focusing on behavioural issues related to cancer treatment and care. Methodological issues in measuring adherence are addressed and suggestions for improving the design of future adherence studies highlighted, of which there is a great need.

Nanotechnology-based drug delivery systems for treatment of oral cancer: a review

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)