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PubMed2001

Resistance of human multidrug resistance-associated protein 1-overexpressing lung tumor cells to the anticancer drug arsenic trioxide.

The human multidrug-resistance protein (MRP1) confers resistance to some heavy metals such as arsenic and antimony, mainly through mediating an increased cellular efflux of metal. However, it was recently suggested that arsenic, used under its trioxide derivative form as anticancer drug, is not handled by MRP1. The aim of the present study was to test this hypothesis in MRP1-overexpressing human lung tumor GLC4/Sb30 cells. Using the cytotoxicity MTT assay, GLC4/Sb30 cells were found to be 10.8-fold more resistant to arsenic trioxide (As2O3) than parental GLC4 cells. MK571, a potent inhibitor of MRP1 activity, almost totally reversed resistance of GLC4/Sb30 cells, but did not alter the sensitivity of GLC4 cells. Moreover, As2O3-loaded GLC4/Sb30 cells poorly accumulated arsenic through an increased MK571-sensitive efflux of metal. Finally, depletion of cellular glutathione levels in buthionine sulfoximine-treated GLC4/Sb30 cells was found to result in increased accumulation and reduced efflux of arsenic in cells exposed to As2O3, outlining the glutathione-dependence of MRP1-mediated transport of the metal. These results indicate that MRP1 overexpression in human tumor cells can confer resistance to As2O3, which may limit the clinical use of this anticancer drug for treatment of MRP1-positive tumors.

ATP-Binding Cassette Transporters↗

PubMed2001

Differential regulation of phosphatidylserine externalization and DNA fragmentation by caspases in anticancer drug-induced apoptosis of rat mammary adenocarcinoma MTLn3 cells.

Caspase activation is a central event in the execution phase of apoptosis and is associated with phosphatidylserine (PS) externalization and DNA fragmentation. We investigated the role of caspase activity in anticancer drug-induced PS externalization and DNA fragmentation in MTLn3 cells. Caspase activation (DEVD-AMC cleavage) occurred in a time- and concentration-dependent manner after exposure to doxorubicin, in association with cleavage of poly(ADP) ribose polymerase and protein kinase C delta, two caspase-3 substrates. Caspase activation was closely followed by oligonucleosomal DNA fragmentation and PS externalization as determined by flow cytometric analysis. Similar observations were made for etoposide and cisplatin. Inhibition of caspases with zVAD-fmk inhibited almost completely doxorubicin-induced DNA fragmentation as well as proteolysis of protein kinase C delta. In contrast, PS externalization induced by doxorubicin was only partly affected by caspase inhibition. Flow cytometric cell sorting demonstrated that DNA fragmentation in the remaining PS positive cells after doxorubicin treatment in the presence of zVAD-fmk was fully blocked. In conclusion, these data indicate that while DNA fragmentation in anticancer drug-induced apoptosis of MTLn3 cells is fully dependent on caspase activity, PS externalization is controlled by both caspase-dependent and caspase-independent pathways.

Adenocarcinoma↗

PubMed2003

Investigation of anticancer mechanism of thiadiazole-based compound in human non-small cell lung cancer A549 cells.

In this study, we have synthesized several compounds and examined their cytotoxic effects on human non-small cell lung cancer A549 cells. We found that GO-13 ((E,E)-2,5-bis[4-(3-dimethyl-aminopropoxy)styryl]-1,3,4-thiadiazole) is the most effective one by the MTT assay. Furthermore, the GO-13-induced apoptotic reaction was identified based on several criteria, such as negative release reaction of lactate dehydrogenase and positive labeling of annexin V and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) techniques. GO-13 induced the apoptosis in A549 cells in a concentration- and time-dependent manner. The data demonstrate that the regulations of p38 mitogen-activated protein kinase and protein kinase C was not involved in the GO-13-mediated mechanism. However, GO-13 significantly induced a down-regulation of Bcl-X(L) expression in a short-term treatment (less than 3hr), whereas stimulated up-regulation of Bax expression in a long-term treatment (24hr) indicating their involvement in GO-13 action. GO-13-mediated apoptosis is also positively correlated with the increase in caspase-3 activity. Worth noting is the fact that GO-13 did not modify the phosphorylation level of Akt/protein kinase B (PKB) until a 24-hr exposure was carried out indicating that the inhibition of Akt/PKB activation was involved in the late-phase apoptosis. Besides the anticancer activity, GO-13 also showed equivalent anti-angiogenic activity in the nude mice angiogenesis model. In summary, we conclude that GO-13 is the most effective anticancer compound in our screening tests. It induced the early-phase apoptosis in A549 cells via the Bcl-X(L) down-regulation, and that of the late-phase through up-regulation of Bax expression as well as inhibition of Akt/PKB activation.

Angiogenesis Inhibitors↗

PubMed1996

Oxaliplatin, tetraplatin, cisplatin, and carboplatin: spectrum of activity in drug-resistant cell lines and in the cell lines of the National Cancer Institute's Anticancer Drug Screen panel.

The present study was designed to explore the activity of platinum compounds in cisplatin-resistant cell lines, the unselected cell lines of the National Cancer Institute's Anticancer Drug Screen, and the potential for use in combination. The activities of four platinum compounds in cisplatin-resistant KB and A2780 cells were investigated. The cells were highly resistant to cisplatin and cross-resistant to carboplatin, but less than one-tenth as resistant to oxaliplatin and tetraplatin. Cellular accumulation of all platinum compounds was decreased in both resistant cell lines. When the activities of cisplatin and oxaliplatin were evaluated in the National Cancer Institute's Anticancer Drug Screen, marked differences were observed. Evaluation of the activity profile using the COMPARE program revealed a different pattern for both agents: the cisplatin activity profile was similar to those of other diamine-platinum compounds, alkylating agents including melphalan, and camptothecin analogs, whereas the activity profile of oxaliplatin resembled those of other "dach" (diaminocyclohexane) platinum compounds and of acridine derivatives. The sensitivity profiles are influenced by the target(s)/mechanism(s) of action and the mechanism(s) of resistance of a drug. The dissimilarity in profiles suggests that these two platinum compounds have a different target(s)/mechanism(s) of action, a different mechanism(s) of resistance, or most likely both. Studies evaluating combinations of cisplatin/oxaliplatin suggest that the activities of these two agents are at least additive and possibly synergistic. Oxaliplatin has a different spectrum of activity and low cross-resistance to cisplatin and should be valuable in cisplatin refractory patients or in combination with cisplatin.

Antineoplastic Agents↗

PubMed1991

Growth factor and oncogene signalling pathways as targets for rational anticancer drug development.

There is a critical need for new targets, in addition to DNA, for anticancer drug development. A recently discovered target is the intracellular signalling pathways that mediate the actions of growth factors and oncogenes on cell proliferation. Two important pathways, the myo-inositol and protein tyrosine kinase signalling pathways are reviewed. Three classes of compounds that modulate myo-inositol signalling are discussed. These are: 1) the D-3-substituted-3-deoxy-myo-inositol analogues that act as antimetabolites of myo-inositol and show selective growth inhibition of some transformed cells; 2) the alkaloid staurosporine that acts as a potent inhibitor of protein kinase C and of platelet-derived growth factor (PDGF) receptor protein tyrosine kinase activity; 3) the ether lipid analogues that block growth factor signalling at several points by acting as inhibitors of protein kinase C, phosphoinositide specific phospholipase C and inositol(1,4,5)trisphosphate-induced Ca2+ release. It is suggested that inhibition of signalling pathways may explain the growth inhibitory effects of these compounds. Other potential signalling target sites for anticancer drug development are discussed.

Alkaloids↗

PubMed2002

Identifying genes related to drug anticancer mechanisms using support vector machine.

In an effort to identify genes related to the cell line chemosensitivity and to evaluate the functional relationships between genes and anticancer drugs acting by the same mechanism, a supervised machine learning approach called support vector machine was used to label genes into any of the five predefined anticancer drug mechanistic categories. Among dozens of unequivocally categorized genes, many were known to be causally related to the drug mechanisms. For example, a few genes were found to be involved in the biological process triggered by the drugs (e.g. DNA polymerase epsilon was the direct target for the drugs from DNA antimetabolites category). DNA repair-related genes were found to be enriched for about eight-fold in the resulting gene set relative to the entire gene set. Some uncharacterized transcripts might be of interest in future studies. This method of correlating the drugs and genes provides a strategy for finding novel biologically significant relationships for molecular pharmacology.

Antineoplastic Agents↗

PubMed2001

Novel functionalized pyrido[2,3-g]quinoxalinones as antibacterial, antifungal and anticancer agents.

A series of twelve novel pyrido[2,3-g]quinoxalinones (3-14), variously substituted at the C-3 position, was synthesized, structurally determined and submitted to a preliminary in vitro evaluation for antibacterial, anticandida and anticancer activities. Results of the antimicrobial screening showed that all compounds, with the exception of 6, 11 and 12, exhibited interesting activity against all strains tested; while compound 10 was found to have encouraging in vitro anticancer activity at a concentration of l0(-4) M.

Anti-Infective Agents↗

PubMed2003

The discovery of a new potential anticancer drug: a case history.

DNA minor groove binders (MGB) represent a class of anticancer agents whose DNA sequence specificity was hypothesized to lead to high selectivity of action. Tallimustine (TAM), a benzoyl nitrogen mustard derivative of distamycin A (DST), showed excellent antitumor activity in preclinical tests, but also a severe myelotoxicity. Novel nitrogen mustard, nitrogen half-mustard and sulfur mustard derivatives of DST showing excellent activity were recently identified and SAR reported. In particular nitrogen half-mustard and sulfur mustard derivatives, as one-arm alkylating agents, represent interesting structural novelties. A further new class of cytotoxic anticancer agents is that of alpha-halogenoacrylamido derivatives of DST-like oligopeptides, which show an activity profile substantially improved in comparison to TAM. In particular brostallicin (PNU-166196), alpha-bromo-acrylamido tetra-pyrrole derivative ending with a guanidino moiety, showed high cytotoxic potency and myelotoxicity dramatically reduced in comparison to TAM and other MGB. Brostallicin binds to the minor groove but appears unreactive in classical in vitro DNA alkylation assays. About the apparent lack of DNA alkylation we speculated that an intracellular nucleophile, e.g. glutathione (GSH), could activate the reactivity of the compound leading to alkylation of DNA in vivo. Evidence of both covalent interaction of brostallicin with plasmidic DNA in the presence of GSH and of enhanced cytotoxicity in cancer cells characterized by high levels of GSH were obtained. Brostallicin was selected for clinical development and is now undergoing Phase II studies.

Animals↗

PubMed2003

Synthesis of 1-(6-chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)semi-carbazides and their transformation into 4-chloro-2-mercapto-N-(4,5-dihydro-5-oxo-4-phenyl-1H-1,2,4-triazol-3-yl)benzenesulfonamides as potential anticancer and anti-HIV agents.

Synthesis of a series of 1-(6-chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)semicarbazides (6-16) and 4-chloro-2-mercapto-N-(4,5-dihydro-5-oxo-4-phenyl-1H-1,2,4-triazol-3-yl)benzenesulfonamides (17-22) were reported. Compounds 7-9, 17, 19-22 were tested at the US National Cancer Institute for their in vitro anticancer and anti-HIV activities. Results of anticancer screening showed moderate activity of 21 and 22, while 19 was found to have encouraging anti-HIV activity at EC(50) = 28.8 microM.

Anti-HIV Agents↗

PubMed1998

Synthesis of substituted 2-ethoxycarbonyl- and 2-carboxyquinoxalin-3-ones for evaluation of antimicrobial and anticancer activity.

A series of variously substituted quinoxalin-3-ones bearing an ethoxycarbonyl or carboxy group in the C-2 position has been prepared and their structures proved by 1H NMR spectroscopy. The obtained compounds were investigated in vitro for antimicrobial and anticancer activities. Preliminary results showed a moderate activity against a few strains of bacteria but no significant anticancer and anti-HIV activity.

Anti-Bacterial Agents↗

PubMedDate not supplied

Quinoxaline chemistry. Part 12. 3-Carboxy-2[phenoxy]-6(7)substituted quinoxalines and N-[4-(6(7) substituted-3-carboxyquinoxalin-2-yl)hydroxy] benzoylglutamates. Synthesis and evaluation of in vitro anticancer activity.

Thirty quinoxalines bearing a substituted phenoxy or hydroxybenzoylglutamate group on position 2, a carboethoxy or carboxy group on position 3 and a trifluoromethyl group on position 6 or 7 of the heterocycle were prepared in order to evaluate the in vitro anticancer activity. Screening over 21 compounds selected at the National Cancer Institute (Bethesda, MD) showed that only few derivatives exhibited a moderate growth inhibition activity on various tumor panel cell lines at 10(-4) molar concentration. The acid derivatives showed no growth inhibition activity. The results obtained in this series seem to indicate that in general carboxy or carboethoxy groups close to O-link with phenyl or benzoyl glutamates on position 2 are detrimental for anticancer activity.

Antineoplastic Agents↗

PubMed2000

Quinoxaline chemistry. Part 13: 3-Carboxy-2-benzylamino-substituted quinoxalines and N-[4-[(3-carboxyquinoxalin-2-yl) aminomethyl]benzoyl]-L-glutamates: synthesis and evaluation of in vitro anticancer activity.

Among a new series of 28 3-carboxy or carbethoxy quinoxalines bearing a substituted benzylamino or N-[4-(aminomethyl)benzoyl]glutamate group on position 2 of the ring and various substituents at C-6, 7 positions, 21 were selected at the National Cancer Institute for evaluation of their in vitro anticancer activity. The results obtained seem to confirm that the carboxy or carbethoxy group on position 3 is not helpful, with a few exceptions, for the anticancer activity.

Antineoplastic Agents↗

PubMed2002

Determination of the release of hydrolyzed demethylcantharidin from novel traditional chinese medicine-platinum compounds with anticancer activity by gas chromatography.

The present paper describes the development of a simple, accurate and reproducible gas chromatographic method for the determination of hydrolyzed demethylcantharidin release from a novel series of traditional Chinese medicine (TCM)-platinum compounds possessing potent anticancer and protein phosphatase 2A (PP2A)-inhibition properties. The salient features of the validated assay were a limit of detection (LOD) of 2 microg/mL, a limit of quantitation (LOQ) of 6 microg/mL, an intra- and inter-day precision of less than 11%, and an accuracy of more than 92%. The developed GC-flame ionization detection (FID) method was successfully utilized for the analysis of hydrolyzed demethylcantharidin, the TCM component that is slowly released from the novel compounds over 24 h, leading to PP2A inhibition. Further structural confirmation was achieved by GC-MS. The GC method is suitable for further mechanistic, pharmacokinetic and metabolic studies of the TCM-Pt compounds that might prove to be new anticancer agents with novel mechanisms of cytotoxic action.

Cantharidin↗

PubMed1985

Analysis of candidate anticancer drugs by thermospray high-performance liquid chromatography-mass spectrometry and by high-resolution mass spectrometry.

Thermospray high-performance liquid chromatography-mass spectrometry (TSP-HPLC-MS) and direct probe high-resolution MS was used to analyze four candidate anticancer drugs. The techniques were used to confirm the identity of the bulk drug and to identify impurities. Analysis by TSP-HPLC-MS resulted in molecular weight information from the separated components using as little as 50 ng of each drug. The high-resolution direct probe MS analysis provided additional structural information and possible empirical formulas for the parent drugs and their impurities. The use of both of these complimentary techniques proved to be very specific for the detection of the anticancer drugs and for postulating the identity of impurities.

3-Deazauridine↗

PubMed1997

Predictors of bone mineral loss in patients with ovarian cancer treated with anticancer agents.

OBJECTIVE: To identify factors predicting bone mineral loss during anticancer chemotherapy. METHODS: Fifteen women (mean age 38.2 +/- 7.8 years; range 30-46 years) with ovarian cancer who had been treated with cisplatin-adriamycin-cyclophosphamide for six cycles every 4 weeks following surgical cytoreductin were studied. Bone mineral density (BMD) of the lumbar spine (L2-L4) was measured by dual-energy x-ray absorptiometry before and after chemotherapy. Fifteen age-matched women whose ovaries had been removed surgically for other reasons. served as controls. None of the patients had received hormonal treatment. The two groups were compared for percentage change of BMD (BMD%) over the same period. In the chemotherapy group, total fat mass, body fat ratio, total lean mass, percent lean, and ration of trunk fat to leg fat were measured by dual-energy x-ray absorptiometry. Lean loss during chemotherapy was also calculated. These variables were compared before and at the end of chemotherapy. Possible correlations of baseline variables with BMD% were determined in univariate and stepwise regression analysis. RESULTS: Mean ( +/- standard deviation) BMD decreased to 87.4 +/- 2.1% after six cycles of chemotherapy and 97.6 +/- 0.4% after 6 months in controls, but the greatest decrease was observed in the chemotherapy group (P < .001). Although baseline lean mass, baseline BMD, body weight, and lean loss during chemotherapy were correlated with BMD% in univariate analysis, baseline lean mass was still significant in stepwise regression analysis. CONCLUSION: Baseline lean mass predicts bone mineral lose with anticancer chemotherapy.

Adult↗

PubMed2003

Regression and regrowth of tumour cords following single-dose anticancer treatment.

In this paper, the evolution of a tumour cord after treatment is investigated by extensive numerical simulations on the basis of a mathematical model developed by Bertuzzi et al. (submitted). The model is formulated in cylindrical symmetry adopting the continuum approach, and takes into account the influence of oxygen level on the proliferation and death rate of cells, the volume reduction due to disgregation of dead cells, and the cell killing effects of radiation and drugs. Some extensions of the model are proposed to represent more accurately the radioresistance of hypoxic cells and the cytotoxic action of anticancer drugs. The steady state of the cord, and the cord evolution from the steady state after the delivery of a single dose of an anticancer agent, are computed for various combinations of model parameters and for different choices of the functions describing the effects of treatments. The results of the numerical computations show that, in spite of its many simplifications, the model behaviour appears to be reasonable in view of the available experimental observations. The model allows having a better insight into some complex treatment-related events, such as cell reoxygenation and repopulation.

Antineoplastic Agents↗

PubMed2000

Resistance mechanisms associated with altered intracellular distribution of anticancer agents.

The resistance of tumor cells to anticancer agents remains a major cause of treatment failure in cancer patients. The term multidrug resistance (MDR) is used to define a resistance phenotype where cells are resistant to multiple drugs with no obvious structural resemblance and with different molecular targets. It is now clear that MDR is always multifactorial. The intracellular drug distribution is modified in many MDR cell lines, leading to increased drug sequestration in acidic vesicles, such as the trans-Golgi apparatus, recycling endosomes, and lysosomes, followed by transport to the plasma membrane and extrusion into the external medium. Since most anticancer agents target DNA or nuclear enzymes, sequestration of drug in cytoplasmic organelles will lead to decreased drug-target interaction and thereby, decreased cytotoxicity. Altered intracellular drug distribution is usually associated with the expression of drug efflux pumps, such as the P-glycoprotein and the multidrug resistance protein. Another common modification in MDR cells is alkalization of the intracellular pH. The relationship between these different resistance mechanisms is reviewed and a model proposed that suggests why these different resistance mechanisms are co-expressed in multiple cell lines.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

A new science-business paradigm in anticancer drug development.

Studies into the molecular mechanisms of cancer have revealed that, with a few exceptions, the disease lacks a specific drug target. Therefore, new anticancer drugs not only take many years and much money to develop but also might not outperform existing drugs. However, what are assumed to be unfavorable hallmarks of cancer, for example drug resistance, can be exploited for selective anticancer therapy and for protection of normal cells. Based on this paradigm, the drug discovery can be complemented by novel use of existing agents and even "failed" drugs. The pharmacological industry could develop low cost, effective therapeutic modalities, by "re-using" already marketed and late-stage products in cancer-selective therapeutic kits.

Antineoplastic Agents↗