Clinical relevance of P-glycoprotein expression in haematological malignancies

Although, generally speaking, haematological malignancies are chemotherapy-responsive tumours and high remission induction rates are obtained, disease-related death is the rule rather than the exception. The appearance of cell populations, resistant to multidrug-based chemotherapy, constitutes the major problem to achieve cures in these patients. Advances in cell biology have partly contributed to the elucidation of different multidrug resistance (MDR) mechanisms, which enable cells to survive the cytotoxic effects of multiple chemotherapeutic agents. Of these resistance mechanisms, the one that is referred to as classical MDR is the most extensively studied, both in the laboratory as well as in patients, and here we will focus on its clinical relevance in haematological malignancies. The classical MDR phenotype is caused by enhanced cellular drug efflux due to increased activity of a membrane-bound glycoprotein (P-glycoprotein) drug pump, that can pump out anthracyclines, anthracenediones, vinca alkaloids and epipodophyllotoxins, thereby actively lowering the intracellular drug concentrations to sublethal levels. As soon as molecular probes for the detection of MDR cells became available, clinical studies were initiated to answer three main questions. Do human tumour cells express P-glycoprotein? If so, is the expression indicative of a bad prognosis, c.q. resistant disease? And last but not least, can we interfere with the P-glycoprotein drug pump in the patient? Clinical data indicate that classical MDR may be involved in the development of drug resistance, especially in some haematological malignancies, such as acute myelocytic leukaemia (AML), non-Hodgkin's lymphomas (NHL), and multiple myelomas (MM). In almost all types of haematological malignancies, either untreated or treated, elevated P-glycoprotein levels have been reported, ranging from low to high. However, the acquisition of clinical MDR associated with P-glycoprotein expression occurs only in those diseases (for example, AML and MM) that are heavily treated with MDR-related drugs, probably by selection of pre-existing P-glycoprotein-expressing malignant cells. Since P-glycoprotein is found to be expressed on the membrane of normal haemopoietic progenitor cells as well, it seems likely that P-glycoprotein-positive haematological tumours develop by malignant transformation of P-glycoprotein-expressing normal haemopoietic counterparts. Especially for AML, convincing data have been reported in the literature to show that P-glycoprotein expression at diagnosis is a bad prognostic factor that predicts refractoriness. Using in vitro model systems for classical MDR, a large number of agents have been identified that can circumvent P-glycoprotein-mediated drug resistance, the so-called resistance modifying agents (RMA). Subsequently, clinical phase I and II studies have been initiated which combine the use of MDR-related drugs in conjunction with RMAs. The overall conclusions from such studies in AML, NHL, and MM are that modulation of drug resistance by RMAs seems promising and that further evaluation in prospective, randomized phase III trials is warranted

Assay method validation of triamcinolone acetonide (TA) to support the investigation of TA-loaded nanoparticles

Theaim of this study was to develop the valid analytical method which used for the assay of triamcinolone acetonide (TA) in the investigation of TA loaded nanoparticle formulations. High Performance Liquid Chromatography(HPLC) method was applied in  his study by using an Econosil column,C1810 m, 250x 4.6mm (Alltech Associates Inc, PA,USA )as the stationary phase. Themobile phase consisted of a composition of acetonitrile (ACN) and 20mM phosphate buffer solution (pH 4.2) in the proportion of 50:50 v/v. The HPLCassay of TA was validated for selectivity, linearity, precision, ecovery (accuracy),sensitivity and stability of TA during the assay. Results showed that the concentration of TA in the sample scan be determined against the standard in the concentration range of calibration curve. The system precision and level of recovery were considered to be acceptable, and the method was selective and sensitive.Key words:triamcinoloneacetonide,assay,validatio

Cytotoxicity of oleandrin isolated from the leaves of Nerium indicum Mill. on several human cancer cell lines

Finding anticancer drugs from natural resources still proceeds. Oleandrin isolated from Nerium indicum Mill. inhibited the growth of mieloma cell line in vitro better than that of vincristine sulphate. This study was aimed to determine the cytotoxic effect of oleandrin on various human cancer cell lines. Cytotoxic test of oleandrin on seven human cancer cell lines was done by SRB-method. The analysis was conducted by comparing the ID50 of oleandrin with that of doxorubicin and cisplatin as positive controls. This result indicated that oleandrin possessed the best cytotoxic effect on breast cancer (MCF7) with ID50 at 8.85 nM. Keywords : Oleandrin, cytotoxicity, human cancer cells, ID5

Sitotoksisitas rimpang temu mangga (Curcuma Mangga Val. & V. Zijp.) dan kunir putih (Curcuma Zedoaria L) terhadap beberapa sel kanker manusia (in vitro) dengan metoda SRB

ABSTRACT Mae Sri Hartati W, Sofia Mubarika, R. L. H. Bolhuis, K. Nooter, R. G. Oostrum, A. W. M. Boersma, Subagus Wahyuono - Cytotoxic effect on human cancer cell using SRB method (in vitro) rimpang temu mangga (Curcuma Mangga Val. & V. Zijp.) dan kunir putih (Curcuma Zedoaria I.). Background: Temu mangga (Curcuma mangga) and kunir putih (Curcuma zedoaria) rhizomes have been utilized by people to treat cancer lately although clinically their activity has not been tested. Objectives: This study is aimed to prove their activity as anticancer on 7 major human cancers cell lines (in vitro), and to evaluate whether these two rhizomes are potential for new anticancer drug. Methods: The two rhizomes were separately extracted with chloroform followed by methanol to give chloroform extracts of C. mangga (CmCh) and C. zedoaria (CzCh)and methanol extracts of C. mangga (CmMe) and C. zedoaria (CzMe) respectively. These extracts were tested their cytotoxic effect on 7 major human cancer cell lines using SRB method (in vitro). Doxorubicin and cisplatin were used as positive controls, and their cytotoxic effects were measured by comparing their ID50 with that of the positive controls. Results: Those four extracts (CmCh, CzCh, CmMe and CzMe) practically did not perform cytotoxic effect on those human cancer cell lines, because the extract\u27s ID50 was far higher than the positive controls on those human, cancers cell lines Conclusion: The C. mangga and C. zedoaria rhizomes did not active as anticancer and they were not pOtential as the source of a new anticancer drug. Key words: anticancer - Curcuma mangga - Curcuma zedoaria - cytotoxic - drug discover