Cardiac Manifestations with Chemotherapeutic Agents: 5 Fluorouracil-Induced Coronary Artery Vasospasm

5-fluorouracil (5-FU) is a fluorinated, pyrimidine analog, antineoplastic agent that is used in the treatment of several solid organ cancers. Cardiotoxicity is uncommon but life-threatening manifestations such as myocardial infarction may manifest owing to 5-FU-induced coronary artery spasm. Administering smaller doses of the drug, more frequently than not, decreases the risk of cardiotoxicity compared to large doses or with continuous infusions. We present a case of ST-segment elevation in a patient without known coronary artery disease who had presented following continuous 5-FU infusion. Coronary angiogram confirmed absence of coronary artery disease and intravenous calcium channel blockers administration was commensurate with the patient’s improvement in symptoms. We discuss the literature on 5-FU and its association with coronary artery spasm, and also briefly review chemotherapy-induced cardiotoxicities to help better prepare internists and other primary health care providers to face similar challenges, particularly of the uncommon but potentially life-threatening manifestations.

EFFECTS OF TNF ALONE OR IN COMBINATION WITH CHEMOTHERAPEUTIC AGENTS ON HUMAN OVARIAN CANCERS IN VITRO AND IN NUDE MICE

Using the tetrazolium (MTT) assay, we examined the cytotoxicities of recombinant human tumor necrosis factor (rhTNF) and five chemotherapeutic agents, namely CTX, 5-FU, VCR, DDP and KSM, on human ovarian cancer cell lines OVCAR3 and CAOV3. The results showed that the cytotoxicities of rhTNF at concentrations of 50-50 000 U / ml on OVCAR3 cell line and CAOV3 cell line exposed to rhTNF for 24 hours were from 14.2% ± 6.8% to 67.2%± 3.0% and from 8.2%± 4.3% to 60.9%±1.3%, respectively. The cytotoxicities of all five chemotherapeutic agents tested on the two cell lines were much lower than that of rhTNF. We also studied the combined antitumor potential of rhTNF with the five chemotherapeutic agents and the results showed that there were various degrees of synergism in cytotoxicities of rhTNF in combination with DDP or KSM on the two cell lines. Based on experiments in vitro, the in vivo antitumor activities of rhTNF, both alone and in combination with KSM, were examined in OVCAR3 cancer transplanted in nude mice. The results showed a considerable antitumor effect of rhTNF when it was used alone and a marked synergistic effect when it was used in combination with KSM on the xenograft tumors.

Drug sensitivity and drug resistance profiles of human intrahepatic cholangiocarcinoma cell lines

AIM: To study the effect of a number of chemotherapeutic drugs on five human intrahepatic cholangiocarcinoma (CCA) cell lines. The expressions of genes that have been proposed to influence the resistance of chemotherapeutic drugs including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), glutathione-S-transferase PI (GSTP1), multidrug resistance protein (MDR1) and multidrug resistance-associated proteins (MRPs) were also determined. METHODS: Five human CCA cell lines (KKU-100, KKU-M055, KKU-M156, KKU-M214 and KKU-OCA17) were treated with various chemotherapeutic drugs and growth inhibition was determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Semi-quantitative levels of gene expression were determined by a reverse transcriptase polymerase chain reaction (RT-PCR). Results of IC_(50) values and the ratios of gene expression were analyzed by linear regression to predict their relationship. RESULTS: Among five CCA cell lines, KKU-M055 was the most sensitive cell line towards all chemotherapeutic drugs investigated, particularly taxane derivatives with IC_(50) values of 0.02-3 nmol/L, whereas KKU-100 was apparently the least sensitive cell line. When compared to other chemotherapeutic agents, doxorubicin and pirarubicin showed the lowest IC_(50) values (＜5 μmol/L) in all five CCA cell lines. Results from RT-PCR showed that TS, MRP1, MRP3 and GSTP1 were highly expressed in these five CCA cell lines while DPD and MRP2 were only moderately expressed. It should be noted that MDR1 expression was detected only in KKU-OCA17 cell lines. A strong correlation was only found between the level of MRP3 expression and the IC_(50) values of etoposide, doxorubicin and pirarubicin (r=0.86-0.98, P＜0.05). CONCLUSION: Sensitivity to chemotherapeutic agents is not associated with the histological type of CCA. Choosing of the appropriate chemotherapeutic regimen for the treatment of CCA requires knowledge of drug sensitivity. MRP3 was correlated with resistance of CCA cell lines to etoposide, doxorubicin and pirarubicin, whereas other chemotherapeutic drugs showed no association. The role of this multidrug resistance-associated protein, MRP3, in chemotherapeutic resistance in CCA patients needs to be further investigated.

Coconut oil nanoemulsion attenuates methotrexate-induced hepatotoxicity and nephrotoxicity in Ehrlich ascites carcinoma-bearing mice

Objective:To evaluate the protective effect of the coconut oil nanoemulsion against methotrexate-induced hepatotoxicity and nephrotoxicity in Ehrlich ascites carcinoma-bearing Swiss albino mice.Methods:Forty mice were divided into four groups.GroupⅠserved as the untreated Ehrlich ascites carcinoma-bearing mice while Ehrlich ascites carcinoma-bearing mice in groupsⅡ–Ⅳreceived an intraperitoneal injection of 0.2 m L/kg coconut oil nanoemulsion,20 mg/kg methotrexate as well as 0.2 m L/kg coconut oil nanoemulsion mixed with 20 mg/kg methotrexate,respectively.The toxicities of the treatments were assessed by determining the complete blood count,performing the serum analysis for liver and kidney functions,evaluating the oxidative status and visualizing histological changes in the liver and kidney tissues.Results:Treatment with methotrexate and coconut oil nanoemulsion markedly diminished the liver parameters including aspartate aminotransferase,alanine aminotransferase,alkaline phosphatase,total protein,direct bilirubin and total bilirubin which were raised by methotrexate treatment(P<0.05).Similarly,creatinine and blood urea nitrogen,as the indicators of kidney function,were dramatically lowered in the combination treatment group compared to the methotrexate group(P<0.05).In addition,treatment with methotrexate and coconut oil nanoemulsion reduced the malondialdehyde and increased catalase,glutathione reductase and superoxide dismutase,in the liver and kidney tissues(P<0.05).The treatment with methotrexate and coconut oil nanoemulsion reduced white blood cell count and increased the hemoglobin amount(P<0.05),but did not cause any change in platelets and red blood cell count.Conclusions:Coconut oil nanoemulsion as a nanocarrier has great potential in reducing the adverse side effects induced by methotrexate.

Formulating etoposide in a nanoemulsion containing polyunsaturated fatty acids potentiates its anti-proliferation and anti-invasion activities against the ovarian cancer cells

Inorporation of etoposide(ETP)into nanoemulsion(NE)containing polyunsaturated faty adids(PUFAS)may potentially augment its antiproliferation efet on the cancer cll The current study aimed to examine the in vitro antitumor activity of a novel formulation(ETP-BC/EP-NE)produced by combining the anticancer drug(ETP)with NE(BCEP-NE)consisting of the blasck currant seed and organic ewening primrose oils.The produced formulas were physically charaterized using 2etasizer measurements.Thelr ceytotoxkc efect was testfied at concentrations ranges from 0.0001 to 5μM using CCK-8.Apoptotic and ant-invasion efects were evaluated using the assays of mitochondrtal membrane potental,annexin V-FITC double staining.DNA fragmentation,and collagen-based cell invasion.According to the zetasizer charaterization,the nano-suspensions of ETP-BC/EP-NE have z-average diameters of 87.63土3.30 nm with an average surface zeta potential of-0.605土0.003 mV.A reduction of 50%in the growth of SK-OV-3 cells was found at a distinetly lower concentration of ETP-BCEP-NE(IlCso=0.04土0.2μM)than that of ETP(ICsu=4.75土0.1μM).Resuts indicated that FTP-BCIEP-NE had a greater apoptotic ffect than FTP on SK-OV-3 cllsl which was attibuted to the larger amount of late apoptotic cells(41.9土1.05%)higher loss of mitochondrial membrane potential,and more intensive fragmented DNA The ETP-BC/EP-NE treatment suppressed the cllular invasion by 55%,whereas EIP impeded the ellular invasion by only 3%,Formulting ETP with PUFAs in NE had ameliorated the efcacy of ETP.

Synthesis, Preliminary Structure-activity Relationships and Biological Evaluation of Pyridinyl-4,5-2H-isoxazole Derivatives as Potent Antitumor Agents

A series of novel pyridinyl-4,5-2H-isoxazole derivatives was synthesized and their chemical structures were characterized by 1H NMR, 13C NMR as well as MS spectroscopic methods, their melting points were also determined. The inhibitory effects of them against breast cancer cell lme（MCF-7） were evaluated by 3-（4,5-dimethyl- 2-thiazolyl）-2,5-diphenyl-2-H-tetrazolium bromide（MTT） procedure in vitro. Most of them possesed potent anti- proliferative activities, among which compounds llc and llj exhibited half maximal inhibitory concentrations（IC50） of 1.9 and 1.5 μmol/L, respectively. These compounds also exhibited potent anti-proliferative activities against both human hepatoma cell line（HepG2） and cervical cancer cell line（HeLa）. Preliminary structure-activity relationship （SAR） information from these compounds can be used to guide further exploration of new compounds with better potency as molecular probes. Further study on the mechanism-of-action of these compounds is under investigation.