Antitumor activities of new iso(thio)cyanates and their nitrogen and sulphur heterocyclic phosphorus derivatives

The cytotoxic activity of Iso(thio)cyanate derivatives and some new organophosphorus compounds were determined,using MTT assay against human hepatocellular carcinoma (HepG2) and adenocarcinoma breast (MCF-7) incomparison with the reference drug 5-flurouracil. All the selected products have been tested and showed concentrationdependent increase in the growth inhibition percentage against HepG2 and MCF-7. Where, the thietane derivativesrevealed anticancer activity with IC50 (20, 8.9 µg/ml) against HepG2 and (20, 10.3 µg/ml) against MCF-7; while,thiazinane compounds showed IC50 (12.7, 32.5 µg/ml) against HepG2 and (20 and 20 µg/ml) against MCF7. The newly synthesized azetidines showed anticancer activity with IC50 (13.5 and 32.5 µg/ml) against HepG2and IC50 (10 and 25.9 µg/ml) against MCF-7 cancer. Moreover, azetidinedione compound exhibited more potentactivity than the azetidinone with both types of cancer cell lines. In addition, the cytotoxic activity of the iso(thio)cyanates, and malonamic acid methyl ester compound were also investigated. 4-Methoxyphenyl isothiocyanate andmethylisothiocyanate, with IC50 (25.9, 12.3 and 40, 20 µg/ml), respectively, against HepG2 and MCF-7 cancer cells.1, 2-Dichloro-4-isocyanato-benzene was similar in potency to the known anticancer drug 5-flurouracil with IC50 (5.3µg/ml) versus 5 µg/ml for 5-flurouracil against MCF-7. While, malonamic acid methyl ester compound had no effecton both types of cancer cell lines.

Farmacogenómica del tratamiento de primera línea en el cáncer gástrico: avances en la identificación de los biomarcadores genómicos de respuesta clínica / Pharmacogenomics of the first-line treatment for gastric cancer: advances in the identification of genomic biomarkers for clinical response to chemotherapy

Debido a la inespecificidad de los síntomas, el cáncer gástrico (CG) es diagnosticado frecuentemente en etapas avanzadas, lo que da cuenta de los altos índices de mortalidad debido a esta neoplasia a nivel mundial. El esquema de tratamiento adyuvante o neoadyuvante en los países occidentales incluye el uso de fluoropirimidinas citotóxicas y compuestos de platino formadores de aductos en el ADN. La respuesta clínica al tratamiento con estos fármacos depende principalmente de la sensibilidad del tumor, la cual a su vez está condicionada por el nivel de expresión de los blancos terapéuticos y de las enzimas de reparación del ADN. Sumado a esto, algunos polimorfismos de línea germinal en genes asociados al metabolismo y a la respuesta a estos fármacos, han mostrado asociación con respuestas pobres y con el desarrollo de eventos adversos, incluso con resultados fatales. La identificación de biomarcadores genómicos, en la forma de polimorfismos genéticos o la expresión diferencial de genes específicos asociados a la respuesta quimioterapeútica ha sido motivo de intensa investigación como base para la aplicación de la farmacogenómica en el establecimiento de una terapia farmacológica racional y personalizada del CG. Sin embargo, ante la eventual aplicación de la farmacogenómica en el ámbito clínico, es necesario establecer el valor pronóstico real de dichos biomarcadores mediante los estudios de asociación genotipo-fenotipo, así como su prevalencia en el contexto de cada población de pacientes. Estos aspectos son indispensables al evaluar la relación costo-efectividad de la introducción de los productos de la medicina genómica predictiva en el tratamiento del CG.

Gastric cancer (GC) is often diagnosed at later stages due to the lack of specificity of symptoms associated with the neoplasm, causing high mortality rates worldwide. The first line of adjuvant and neoadjuvant treatment includes cytotoxic fluoropyrimidines and platin-containing compounds which cause the formation of DNA adducts. The clinical outcome with these antineoplastic agents depends mainly on tumor sensitivity, which is conditioned by the expression level of the drug targets and the DNA-repair system enzymes. In addition, some germ line polymorphisms, in genes linked to drug metabolism and response to chemotherapy, have been associated with poor responses and the development of adverse effects, even with fatal outcomes in GC patients. The identification of genomic biomarkers, such as individual gene polymorphisms or differential expression patterns of specific genes, in a patient-by-patient context with potential clinical application is the main focus of current pharmacogenomic research, which aims at developing a rational and personalized therapy (i.e., a therapy that ensures maximum efficacy with no predictable side effects). However, because of the future application of genomic technologies in the clinical setting, it is necessary to establish the prognostic value of these genomic biomarkers with genotype-phenotype association studies and to evaluate their prevalence in the population under treatment. These issues are important for their cost-effectiveness evaluation, which determines the feasibility of using these medical genomic research products for GC treatment in the clinical setting.

Oxaliplatin/5-FU without Leucovorin Chemotherapy in Metastatic Colorectal Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Fluorouracil (5-FU) and leucovorin combination therapy have shown synergistic or additive effect against advanced colorectal cancer, but the frequency of mucositis and diarrhea is increased. Most previous studies have used high dose leucovorin (300~500 mg/m2). However, some studies of oxaliplatin and 5-FU with low-dose or high-dose leucovorin in Korea have shown similar response rates. Therefore, we studied the necessity of leucovorin and evaluated the objective tumor response rates and toxicities of a regimen of oxaliplatin and 5-FU without leucovorin every 2 weeks in metastatic colorectal cancer patients. MATERIALS AND METHODS: Twenty-four patients with metastatic colorectal cancer were enrolled between January 2002 and March 2003. Patients received 85 mg/ m2 of oxaliplatin on day 1, a bolus 5-FU 400 mg/m2 on day 1 and a continuous 5-FU infusion at 600 mg/m2/ 22 hours days 1 and 2, every 2 weeks. RESULTS: Of the 24 patients treated, 17 patients received previous 5FU with leucovorin and/or other chemotherapy. Three patients could not be evaluated. Five partial responses were observed with overall response rate of 21% (n=24). Of the previous chemotherapy group (n= 17), 4 partial responses were observed with response rate of 24%. Median overall survival was 18 months (range 4~32 months) and median progression free survival was 4 months (range 2~6 months). This regimen was well tolerated and only 1 grade 3 anemia was observed. CONCLUSION: Oxaliplatin/5-FU combination therapy without leucovorin achieved a relatively high response rate even in patients resistant to the previous 5-FU chemotherapy, and toxicity was minimal.

Effect of caspase-9 in the apoptosis of hepatoma cells induced by flurouracil / 中国普通外科杂志

Objective To determine the effect of caspase 9 in the apoptosis of hepatoma cells induced by flurouracil , and to investigate the activity alteration and proteolytic cleavage of caspase 9. Methods The human hepatoma HepG2 cells were treated with flurouracil for 2,4,8,16,24h respectively. The caspase 9 activity was detected using caspase 9 Fluorescent Assay Kit.Proteolytic cleavage of caspase 9 was analyzed by Western blot.The apoptotic rates of HepG2 cells induced by flurouracil with or without caspase 9 inhibitor treatment were measured by flow cytometry. Results Four hours after being treated with flurouracil, the caspase 9 activity in HepG2 cells increased gradually and reached the peak at 16h.Compared with the control group, the difference was significant (P