Synthesis and evaluation of apoptosis induction of thienopyrimidine compounds on KRAS and BRAF mutated colorectal cancer cell lines.

Monoclonal antibodies (MoAb) and tyrosine kinase inhibitors (TKI) targeting the EGFR (Epidermal Growth Factor Receptor) pathways are currently used in colorectal cancer treatment. Despite the improvement of median overall survival, resistance is observed notably due to KRAS and BRAF gene mutations. We synthesized four series of thienopyrimidines whose scaffold is structurally close to TKI used in clinical practice. We evaluated apoptosis induced by these compounds using flow cytometry on KRAS and BRAF mutated cell lines. Our results confirm that the mutated cell lines (HCT116 and HT29) are more resistant to apoptosis than the non-mutated cell line (Hela). Interestingly, among the 13 compounds tested, three of them (5b, 6b and 6d) and gefitinib exhibited a noteworthy pro-apoptotic effect, especially on mutated cell lines with an IC(50) value between 70 and 110µM. These three compounds seem particularly attractive for the development of novel treatments for colorectal cancer patients harboring EGFR pathway mutations.

Synthesis and study of antiproliferative activity of novel thienopyrimidines on glioblastoma cells.

The receptor tyrosine kinases (for example EGFR, PDGFR, VEGFR) are a transmembrane protein family which plays a crucial role in tumor growth, survival, metastasis dissemination and angiogenesis. During the past 10 years, many tyrosine kinase inhibitors (TKIs) have been approved for cancer treatment (imatinib, gefitinib, erlotinib, sunitinib, sorafenib). These compounds generally possess a pyrrolo- or pyrimido- pyrimidine scaffold or approaching molecular structure. We synthesized 10 thienopyrimidine compounds (including 5 newly synthesized) whose scaffold is very similar to the agents cited above. The cytotoxicity of these agents was evaluated using a MTT assay and a flow cytometry technique on glioblastoma cell lines. Two compounds showed a similar cytotoxicity to the standard anti-EGFR gefitinib (IC50: gefitinib=51.9 microM, 6b=61.8 microM, 6c=41.2 microM), suggesting a blockade of the EGFR pathway by binding to the TK receptor.

Cancer mortality in patients with schizophrenia: an 11-year prospective cohort study.

BACKGROUND: Schizophrenia has been associated with a rate of premature mortality that is 2 to 3 times higher than that in the general population. Although the role of cancer in this excess mortality remains unclear, previous incidence or mortality studies found contradictory results. METHODS: In 1993, a large prospective study was initiated in a cohort of 3470 patients with schizophrenia to examine cancer-related mortality and predictors. Standardized mortality ratios (SMRs) were calculated, adjusting for age and sex relative to a representative sample of the French general population. RESULTS: During the 11-year follow-up, 476 (14%) patients died; the mortality rate was thus nearly 4-fold higher than in the general population. Cancer was the second most frequent cause of mortality (n=74), with a global SMR of 1.5 (95% confidence interval [95% CI], 1.2-1.9). For all cancers, the SMRs were 1.4 (not significant) for men and 1.9 (95% CI, 1.4-2.8) for women. For men, lung cancer was the most frequent localization (n=23; 50%), with an SMR of 2.2 (95% CI, 1.6-3.3). For women, breast cancer was the most frequent localization (n=11; 39%), with an SMR of 2.8 (95% CI, 1.6-4.9). In comparison with patients who did not die of cancer, there were 2 significant baseline predictors of death by lung cancer in the final logistic regression model: duration of smoking and age>38 years. CONCLUSIONS: The results of the current study demonstrated an increased risk of mortality by cancer in patients with schizophrenia, especially for women from breast cancer and for men from lung cancer.

Ten-year prospective follow-up study of the mortality by suicide in schizophrenic patients.

This ten-year follow-up study examined the prevalence and the most relevant baseline predictors of suicide in schizophrenic patients. In 1993, 3470 patients meeting the ICD-10 criteria for schizophrenia were assessed. We used national death certificate data to identify patients that had died by suicide for each year included in the study. In this way, we calculated standardized mortality ratios, adjusting for age and sex relative to the general population. We used Cox's proportional hazards models to investigate potential sociodemographic and clinical risk factors. There were 141 suicides in the cohort during the follow-up period, corresponding to a risk of suicide that was approximately 16 times higher than that of the general population. Women had slightly higher standardized mortality ratios than men. Suicide was the cause of death in more than half (53.9%) of deaths occurring during the first year of follow-up and nearly one-third (31.8%) of those occurring in the ten-year period of the study. There were four significant baseline predictors of suicide remaining in the final logistic regression model: male gender, drug abuse, previous suicide attempts, and short duration of illness. Sex, age, history of suicide attempt should be particularly considered in the assessment of suicide risk in schizophrenic patients. Our findings also emphasize the need for detection and effective management of associated comorbid drug abuse.

Predictive factors of the number and the dose of anti-psychotics in a cohort of schizophrenic patients.

BACKGROUND: Anti-psychotic prescription in schizophrenia is characterised in Europe by frequent associations and high doses. Nevertheless, few longitudinal epidemiological studies have explored anti-psychotic prescriptions. AIM: (1) To describe the evolution of prescription patterns across time; (2) to determine risk factors for prescription of high doses of anti-psychotics and for anti-psychotic combinations. MATERIALS AND METHODS: Three thousand four hundred seventy three subjects were included in 1993. Data collected in 1993 and subsequently in 1996 and 1999, provided information on demographics, clinical status and prescription. In 1996, the response rate was 68.5% and 56.7% in 1999. RESULTS: The number of anti-psychotics prescribed slightly decreased across time, while doses remained high for one-third of the patients. The factors predicting dose were: dose at previous evaluation, class of anti-psychotic and clinical severity. The factors predicting the number of anti-psychotics were: previous number and class of anti-psychotic and clinical severity. CONCLUSION: Higher dosage and combinations were related more to physicians' habits than to patient characteristics, as is frequently observed in chronic disease.

Neuroleptics and mortality in schizophrenia: prospective analysis of deaths in a French cohort of schizophrenic patients.

OBJECTIVE: The putative role of neuroleptics in the known excess mortality of subjects with schizophrenia remains disputed. The aim of this study was to assess the link between mortality and the class of neuroleptic. METHOD: Causes of death (suicide, cardiovascular, etc.) and exposure to neuroleptics were studied in a cohort of 3474 patients with schizophrenia followed from 1993 to 1997. RESULTS: From 1993 to 1997, 178 patients died. The risk of all-cause death (OR=1.59; 95% CI 1.02-2.50; p=0.04), and suicide (OR=2.22; 95% CI 1.24-3.97; p=0.006) were increased in users of thioxanthenes (alone or associated with other drugs), and increased risk of "other causes" of death was associated with use of atypical neuroleptics (OR=2.06; 95% CI 1.15-3.70; p=0.0016). CONCLUSION: Our findings suggest the existence of association between certain classes of neuroleptics and death, all cause or specific. This could be related to the drug itself or to patient selection.