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PubMed2005

4-methylumbelliferone, a hyaluronan synthase suppressor, enhances the anticancer activity of gemcitabine in human pancreatic cancer cells.

Hyaluronan (HA) is a ubiquitous, major component of the pericellular matrix and is necessary for various physiological processes. It plays a very important role in biological barriers. We previously reported that 4-methylumbelliferone (MU) inhibits HA synthesis and pericellular HA matrix formation in cultured human skin fibroblasts, Streptococcus equi FM100, and B16F10 melanoma cells. We hypothesized that MU-mediated inhibition of HA synthesis and pericellular HA matrix formation would increase the efficacy of anticancer drugs. We have already demonstrated in vitro, using a sandwich binding protein assay and a particle exclusion assay, that MU inhibits HA synthesis and formation of the pericellular HA matrix, respectively, in human KP1-NL pancreatic cancer cells. AlamarBlue assay revealed that the anticancer effect of gemcitabine in KP1-NL cells was increased by pretreatment with MU. In vivo simultaneous administration of MU and gemcitabine to tumor-bearing mice with severe combined immunodeficiency disease (SCID) decreased the size of the primary and metastatic tumors more than did gemcitabine alone. These data strongly suggest that a combination of MU and gemcitabine is effective against human pancreatic cancer cells. MU may have potential as a chemosensitizer and may provide us with a new anticancer strategy.

Animals↗

PubMed1998

Preclinical pharmacology of the natural product anticancer agent 10-hydroxycamptothecin, an inhibitor of topoisomerase I.

PURPOSE: 10-Hydroxycamptothecin (HCPT) is an indole alkaloid isolated from a Chinese tree, Camptotheca acuminata, and has a wide spectrum of anticancer activity in vitro and in vivo mainly through inhibitory effects on topoisomerase I. HCPT has been shown to be more potent and less toxic than camptothecin and has recently undergone clinical trials. To determine how HCPT might be best used as an anticancer agent, preclinical studies of the pharmacokinetics, tissue distribution, metabolism and elimination of HCPT in rats were undertaken. METHODS: HCPT was administered to rats by i.v. bolus injection at doses of 1, 3, and 10 mg/kg body weight. HCPT (lactone and carboxylate) and its metabolites in plasma, urine, feces, and various tissues were quantitated by reversed-phase HPLC. Pharmacokinetic parameters were then estimated. RESULTS: Following i.v. administration at doses of 3 or 10 mg/kg, the plasma concentration-time profile for lactone HCPT could be best described by a three-compartment model, with terminal elimination half-lives of 140.4 and 428.6 min, respectively. A two-compartment model was used to fit the plasma concentration-time curve at 1 mg/kg, with a terminal elimination half-life of 30.5 min. Carboxylate HCPT had a longer half-life than the lactone form of HCPT. During the initial 6 h after dosing, urinary excretion was the major route of elimination, and fecal excretion became the major route of elimination thereafter. HCPT was widely distributed to various tissues including the enterohepatic system, kidney, and bone marrow. The lactone form of HCPT was detectable in various tissues examined up to 72 h after dosing at all the three test doses. HCPT glucuronides were present in plasma, urine, feces and various tissues. No significant toxicity was observed at doses of 1 or 3 mg/kg. Polyuria and hematuria were observed only during the initial 3 h after dosing at 10 mg/kg. CONCLUSIONS: Prolonged elimination of HCPT in vivo may have a significant impact on its therapeutic effects. HCPT is metabolized to its carboxylate form and glucuronides. Dose-dependent toxicity was observed with i.v. administration of HCPT. The results of this study should be useful in the design of future human trials with this anticancer drug.

Animals↗

PubMed2000

Effects of protein binding on the in vitro activity of antitumour acridine derivatives and related anticancer drugs.

PURPOSE: We set out to measure drug binding to serum proteins. These have been shown to reduce the free plasma concentrations of a number of anticancer drugs, particularly of those of complex organic structure, in both experimental studies and clinical trials. METHODS: We have used cultures of murine Lewis lung carcinoma cells as sensors of available drug to measure the effects of two drug-binding plasma proteins, alpha-acid glycoprotein (AAG) and human serum albumin (HSA), as well as of bovine serum albumin (BSA) on drug activity. RESULTS: The concentrations required for 50% growth inhibition (IC50 values) of a number of anticancer drugs were found to be linear functions of the added proteins. Assuming that cells respond to free drug, the data provide estimates of the product K x n, where K is the binding constant of the protein and n is the number of drug binding sites per protein molecule. Amsacrine, the amsacrine analogue asulacrine, camptothecin, DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide), doxorubicin, etoposide, mitoxantrone, paclitaxel and vincristine were tested. The K x n values for AAG were 30, 2,400, 8.7, 340, 29, 290 x 10(3) M(-1) and 120 x 10(3) M(-1), respectively, and the K x n values for HSA were 16, 580, 530, 10, 6.2, 4.3 x 10(3) M(-1) and 0.0 x 10(3) M(-1), respectively. The combined data allowed the estimation of free fractions of drug in plasma, assuming that AAG and HSA contributed most to protein binding. The data were in general comparable with that reported using equilibrium dialysis and ultrafiltration. Data for drug binding to BSA were different from those for HSA, in some cases by a large factor with values for HSA generally higher. The applicability of the method to analogue development was illustrated by examining the binding to AAG of a series of DACA analogues, and binding was found to be primarily related to lipophilicity. CONCLUSION: IC50 determinations provide a rapid means of estimating drug binding to plasma proteins and have utility in the assessment of new anticancer drugs.

Amsacrine↗

PubMed2002

Evaluation of the histoculture drug response assay as a sensitivity test for anticancer agents.

PURPOSE: To investigate whether the effects of anticancer agents are able to be predicted, the results of sensitivity tests on anticancer agents were compared with the results of preoperative chemotherapy. METHODS: Biopsies were taken from 25 patients with esophageal cancer and 10 with gastric cancer, before chemotherapy, and the drug sensitivity was determined after culturing for 1 week. The chemotherapy consisted of low-dose cis-diamino-dichloroplatinum + 5-fluorouracil, and its clinical effect was determined after 3 or 5 weeks. RESULTS: Sensitivity was determined in 20 of the esophageal cancer patients and 8 of the gastric cancer patients, accounting for 80% of all the patients. Of the 11 patients judged to have sensitivity by the histoculture drug response assay (HDRA), 7 had a partial response, and of the 17 judged to have no sensitivity, 16 had a minor response or no change (NC). It was thus demonstrated that predictions of the effect of anticancer agents could be made with considerable accuracy using HDRA. CONCLUSION: The prognosis of the NC patients was poor, and distant metastasis, thought to be an adverse effect, soon appeared. From the viewpoint of both medical costs and patient quality of life, treatments other than preoperative chemotherapy should be selected for patients assessed to have NC. We believe that these sensitivity tests should be introduced clinically.

Adult↗

PubMed2001

Apatite cement containing cis-diamminedichloroplatinum implanted in rabbit femur for sustained release of the anticancer drug and bone formation.

To treat malignant bone tumors, anticancer drugs are administered systemically, simultaneously with surgical therapy. However, drugs administered systemically have considerable invasive action on bone and other organs, and are also associated with various side effects. A bone-cementing material that can maintain high concentrations of anticancer drug at local sites and which can improve local structural weakness after tumor resection would constitute an ideal therapeutic means of treating malignant bone tumors. We therefore applied the concept of a drug delivery system and developed an implant containing calcium phosphate cement and the anticancer drug, cis-diamminedichloroplatinum (CDDP). The results of a sustained release test showed that the in-vitro cumulative release ratio of an implant containing 20% CDDP was over 60%, and a release rate of 0.1 mg/day was maintained. Experiments in vivo, using adult rabbits implanted with 10% CDDP, showed that the platinum (Pt) concentration in local bone marrow was an average 3200 microg/tissue.g 6 weeks after implantation. The concentration of Pt in the systemically administered group was 0.2 microg/tissue.g at 6 weeks. The Pt concentrations in other organs of the implanted group were: 3 microg/tissue.g or less in the kidney, and 2 microg/tissue.g or less in liver. These values were lower than those in the systemically administered group (3.5 and 2.1 microg/tissue.g, respectively). Local bone formation was observed by 12 weeks after implantation. Our implant maintained high Pt concentrations at local sites and the bone that formed reinforced the implant.

Animals↗

PubMed2003

Markovian chemicals "in silico" design (MARCH-INSIDE), a promising approach for computer-aided molecular design I: discovery of anticancer compounds.

A simple stochastic approach, designed to model the movement of electrons throughout chemical bonds, is introduced. This model makes use of a Markov matrix to codify useful structural information in QSAR. The self-return probabilities of this matrix throughout time ((SR)pi(k)) are then used as molecular descriptors. Firstly, a calculation of (SR)pi(k) is made for a large series of anticancer and non-anticancer chemicals. Then, k-Means Cluster Analysis allows us to split the data series into clusters and ensure a representative design of training and predicting series. Next, we develop a classification function through Linear Discriminant Analysis (LDA). This QSAR discriminates between anticancer compounds and non-active compounds with a correct global classification of 90.5% in the training series. The model also correctly classified 86.07% of the compounds in the predicting series. This classification function is then used to perform a virtual screening of a combinatorial library of coumarins. In this connection, the biological assay of some furocoumarins, selected by virtual screening using the present model, gives good results. In particular, a tetracyclic derivative of 5-methoxypsoralen (5-MOP) has an IC50 against HL-60 tumoral line around 6 to 10 times lower than those for 8-MOP and 5-MOP (reference drugs), respectively. Finally, application of Iso-contribution Zone Analysis (IZA) provides structural interpretation of the biological activity predicted with this QSAR.

Computer Simulation↗

PubMed2006

Low dose leflunomide activates PI3K/Akt signalling in erythroleukemia cells and reduces apoptosis induced by anticancer agents.

Rheumatoid arthritis (RA) is characterized by persistent joint synovial tissue inflammation. Leflunomide is an immunomodulatory agent that has been approved for treatment of active RA. In the past few years, uses other than RA treatment have appeared. Leflunomide has been reported to show antitumor potential through inhibition of cancer cell proliferation. We thus tested the antiproliferative potential of leflunomide on HEL and K562 erythroleukemia cells. The findings summarized in this report demonstrate for the first time that low dose leflunomide prolonged survival and reduced apoptosis induced by several anticancer agents in erythroleukemia cells. We showed that in treated cells, leflunomide reduced the signalling pathways involved in promoting apoptosis by reducing p38 MAPK and JNK basal activity. On the other hand, leflunomide transiently activated the ERK signalling pathway and induced a sustained activation of Akt. We also showed that leflunomide reduced caspase-3 activity and DNA fragmentation induced by anticancer agents. By using an inhibitory strategy, we showed that inhibition of Akt activation but not ERK abolished the protective effect of leflunomide. Thus our findings suggested that leflunomide reduced apoptosis induced by anticancer agents through PI3K/Akt signalling activation.

Antineoplastic Agents↗

PubMed2005

Denbinobin-mediated anticancer effect in human K562 leukemia cells: role in tubulin polymerization and Bcr-Abl activity.

Denbinobin (5-hydroxy-3,7-dimethoxy-1,4-phenanthraquinone) has been reported to exhibit anti-tumor and anti-inflammatory activity. Nevertheless, the anti-tumor mechanism of denbinobin remains unclear. In the present study, we evaluated the anticancer activity of denbinobin in human myelogenous K562 leukemia cells. In accordance with the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay, we demonstrated that denbinobin inhibited cell viability in a concentration-dependent manner with an IC50 value of 1.84 microM. Cell cycle analysis illustrated that exposure of denbinobin caused a G2/M phase accumulation in a time-dependent manner. Tubulin polymerization in cells was apparently enhanced by denbinobin, implying that denbinobin might have a regulatory role in tubulin/microtubule. Furthermore, denbinobin significantly suppressed the expression of Bcr-Abl and phosphorylation of CrkL, a crucial tyrosine kinase and an adaptor protein in chronic myeloid leukemia, respectively. Denbinobin also markedly enhanced CD11b expression after a long-term treatment, suggesting that denbinobin might play a role in facilitating differentiation in K562 cells. In summary, we have demonstrated that denbinobin displays anticancer effects in K562 cells through the increase of levels of tubulin polymerization and deregulation of Bcr-Abl signaling. Our data demonstrate that denbinobin could be a potential anticancer lead compound for further development.

Anthraquinones↗

PubMed1992

Studies on the molecular pharmacology of GR63178A. A novel pentacyclic pyrolloquinone anticancer drug.

GR63178A (NSC D611615) is the second pentacyclic pyrolloquinone to be evaluated clinically as an anticancer drug. Its mechanism of action is unknown but may be related either to its quinone group or planar ring system. In this report we have investigated the ability of GR63178A to bind non-covalently to DNA, inhibit topoisomerase II and undergo reduction to reactive free radical species. Using two DNA duplexes, a 12-mer oligonucleotide which is a preferred sequence for minor groove binders and a hexamer which is a preferred sequence for intercalators, no evidence of significant binding with GR63178A was found. Neither GR63178A nor GR54374X (its 9-hydroxy metabolite) inhibited purified human topoisomerase II in a decatenation assay. Free radical chemistry was studied by both pulse radiolysis and ESR spectroscopy as well as by in vitro drug incubations with NADPH-fortified rat liver microsomes and purified cytochrome P450 reductase. The one-electron reduction potential of GR63178A was -207 mV +/- 10 which is much more positive than other quinone-containing anticancer drugs such as doxorubicin, mitomycin C and mitozantrone. GR63178A underwent enzyme-catalysed quinone reduction more readily than doxorubicin but produced significantly fewer reactive oxygen species. No evidence was detected of drug-induced, radical-mediated DNA damage in vitro using pBR322 plasmid DNA. Disproportionation of the GR63178A semi-quinone free radical proceeded with a rate constant of 1 x 10(9) M-1 sec-1 under anaerobic conditions, one order of magnitude faster than doxorubicin. The preferential disproportionation of the semi-quinone may explain our inability to detect a free radical signal by ESR. The hydroquinone of GR63178A was stable and exhibited strong visible absorption with a bathochromic shift of 120 nm over the parent drug. These unusual properties may be due to the hydroquinone undergoing a form of keto-enol tautomerization. Thus, GR63178A free radical formation does not appear to result in significant drug activation. In conclusion, GR63178A is unlikely to mediate its antitumour activity by DNA binding, topoisomerase II inhibition or free radical formation in direct contrast to similar anthracycline- and anthraquinone-based anticancer drugs.

Animals↗

PubMed1995

Binding of anticancer drugs to human serum albumin studied by reversed-phase chromatography.

The interaction of eight commercial anticancer drugs with human serum albumin (HSA) was studied by charge-transfer reversed-phase thin-layer chromatography in neutral, acidic, basic and ionic environments (NaCl and CaCl2) and the relative strength of interaction was calculated. Each drug interacted with HSA in a neutral environment, and the pH and the presence of mono- and divalent cations markedly affected the strength of interaction. The capacity of anticancer drugs to interact with HSA depended considerably on their molecular structure. Various multivariate statistical methods such as principal component analysis and cluster analysis indicated that the steric parameters of anticancer drugs have a considerable impact on their capacity to bind to HSA. The influence of electronic parameters on the HSA-drug interaction was of secondary importance.

Antineoplastic Agents↗

PubMed1989

Anticancer drugs. II. Synthesis and biological evaluation of spin labeled derivatives of podophyllotoxin.

The spin labeled derivatives of podophyllotoxin, 4-[4''-(2'',2'',6'',6''-tetramethyl-l''-piperidinyloxy)amino] -4'-demethylepipodophyllotoxin(GP-7,3) and N-podophyllic acid-N''-[4-(2,2,6,6-tetramethyl-l-piperidinyloxy)] thiosemicarbazide(GP-4,5) were synthesized and tested for their anticancer activity against the mouse solid tumors S180 and HepA in vivo, and the mouse lymphocytic leukemia L1210 and human stomach carcinoma SGC-7901 cells in vitro. At equitoxic concentrations, the anticancer activity of GP-7(3) was found to be similar to that of the clinically used VP-16(2). The toxicity of GP-7(3) (LD50231.2 mg/Kg) is 3.3 times lower than that of VP-16 (LD50 69.5 mg/Kg). GP-7(3) exhibits low subchronic toxicity. The total chemical yield of GP-7 (26%) is 4 times higher than that of VP-16 (6%) (based on podophyllotoxin). Therefore, GP-7(3) seems to be a promising new entry into the podophyllotoxin class of anticancer drugs.

Animals↗

PubMed1992

Tumoricidal activity of Kupffer cells augmented by anticancer drugs.

The effect of Mitomycin-C (MMC) and Adriamycin (ADM) on the antitumor-associated function of Kupffer cells was examined. MMC and ADM enhanced the production of superoxide by Kupffer cells in cultures at low concentrations likely to occur in clinical use. The expression of interleukin-2 receptor, Ia antigen and asialoGM1 antigen, measured by flowcytometry, was increased by contact with MMC. Growth inhibition of AH130, rat ascites hepatoma, and P815, murine mastocytoma, by Kupffer cells treated with anticancer drugs was greater than that by Kupffer cells alone or anticancer agent alone. These results show that MMC and ADM activate Kupffer cells, leading to synergistic antitumor activity. The results suggest that some anticancer agents act through immunological mechanisms as well as through direct antineoplastic activity.

Animals↗

PubMed1995

DNA topoisomerase II isozymes involved in anticancer drug action and resistance.

DNA topoisomerase II is a major protein of the nuclear matrix. The enzyme appears to have a central role in both DNA organization and replication. The importance of nuclear matrix topoisomerase II alpha as a target for certain anticancer agents was evaluated in CEM human leukemia cells. Studies were done to determine the extent to which the alpha (170 kDa) and beta (180 kDa) isozymes of topoisomerase II form covalent enzyme-DNA complexes in whole cells and in the nuclear matrix and nonmatrix fractions of CEM cells that are either sensitive or resistant to topoisomerase II-active anticancer agents. Topoisomerase II alpha was detected in both the high salt-soluble (nonmatrix) and matrix fractions of nuclei from parental CEM cells. Most of the matrix topoisomerase II alpha was tightly bound to DNA in cells incubated with VM-26. In contrast, topoisomerase II beta was detected only in the high salt-soluble (nonmatrix) fraction of the nucleus. The subnuclear distribution of the alpha and beta topoisomerase II isozymes in CEM/VM-1 cells resistant to topoisomerase-active drugs was similar to that in drug-sensitive CEM cells. However, the amount and activity of topoisomerase II alpha in nuclear matrices of CEM/VM-1 cells were decreased 3- to 6-fold relative to that of CEM cells. The differences observed in the subnuclear distribution and DNA binding pattern of the topoisomerase II isozymes support the hypotheses that each isozyme has a distinct cellular function. Furthermore, these results provide evidence that topoisomerase II alpha is the nuclear matrix target for VM-26, and that depletion of the nuclear matrix isozyme contributes to cellular resistance to this anticancer agent.

Adenosine Triphosphate↗

PubMed1991

Effects of amsacrine in combination with other anticancer agents in human acute lymphoblastic leukemia cells in culture.

Effects of amsacrine in combination with other anticancer agents at ID80 were evaluated by cell growth assay using a human T-cell leukemia cell line (MOLT-3). The data were analyzed with the aid of an improved isobologram, using the concept of an envelope of additivity. A supra-additive effect was observed for amsacrine in combination with cytosine arabinoside and mitoxantrone. An additive effect was observed in its combinations with bleomycin, CPT-11, cisplatin, daunorubicin, doxorubicin, etoposide, 5-fluorouracil, homoharringtonine, mitomycin C, or vincristine. 6-Mercaptopurine had an additive effect with amsacrine at ID80 but a sub-additive to protective effect at ID90. A sub-additive to protective effect was shown for amsacrine in combination with methotrexate. These data suggest that cytosine arabinoside and mitoxantrone are the best of the anticancer agents we studied for use in combination with amsacrine. Bleomycin, cisplatin, CPT-11, doxorubicin, cytosine arabinoside, homoharringtonine, mitomycin C, and vincristine also yielded favorable results when administrated simultaneously with amsacrine. Simultaneous administration of amsacrine with 6-mercaptopurine and methotrexate is not appropriate. If amsacrine is combined with 6-mercaptopurine and methotrexate, other suitable schedules should be explored. These results may provide a rationale for the design of clinical protocols combining amsacrine with other anticancer agents.

Amsacrine↗

PubMedDate not supplied

Signalling pathways as targets for anticancer drug development.

Intracellular signalling pathways mediating the effects of oncogenes on cell growth and transformation offer novel targets for the development of anticancer drugs. With this approach, it may be sufficient to target a component of the signalling pathway activated by the oncogene rather than the oncogene product itself. In this review, the abilities of some antiproliferative drugs to inhibit signalling targets are considered. There are some anticancer drugs already in clinical trial that may act by inhibiting signalling targets, as well as drugs in preclinical development. Some problems that may be encountered in developing this new class of anticancer drugs are discussed.

Antineoplastic Agents↗

PubMed1991

In vitro studies on genotoxicity and cytotoxicity of the anticancer drugs cisplatin and cofplaton, a caffeine-8-ether plus cisplatinum compound.

The cytotoxic and genotoxic properties of the newly designed anticancer drug 'cofplaton' were investigated. Since cofplaton is a cisplatin (CDDP) plus caffeine compound, the widely applied anticancer drug CDDP alone or in combination with caffeine was studied in parallel. As measured by the MTT test the cytotoxicity of the two drugs was comparable, but cofplaton exhibited significantly fewer genotoxic side effects than CDDP in the chromosome aberration test as well as in the SCE assay. First results from animal studies indicate that cofplaton exerts antitumor activity comparable to CDDP. Because of its relatively low genotoxicity, cofplaton seems to be a promising drug in human anticancer therapy.

Animals↗

PubMed1987

Sensitivity of normal human bone marrow myeloid progenitor cells to anthracycline, cisplatin, anthracene and flavone acetic acid derivatives, and its relevance for the prediction of human plasma concentrations of anticancer drugs.

Many in vitro investigations with anticancer agents are performed at concentrations equal to the peak concentrations or fractions of the peak concentrations achieved in human plasma after administration of these agents. In an effort to develop an in vitro test capable of predicting these peak plasma concentrations prior to the completion of pharmacokinetic studies, the effect of several classes of anticancer agents against normal human bone marrow myeloid progenitor cells (CFU-GM) was studied. The investigated agents included anthracycline antibiotics, cisplatin and its analogs, anthracene derivatives and two flavone acetic acid derivatives. The CFU-GM were exposed to these agents for 30-60 min. An exponential relationship between drug concentration and CFU-GM growth was observed for all compounds with the exception of the flavone acetic acid derivatives which were inactive. For the latter two compounds, an inhibition of CFU-GM growth was observed after continuous exposure. When compared to the plasma concentrations after parenteral administration of these agents, there was a very good agreement between 1/10 of the peak plasma concentration and the concentration inducing a 90% inhibition of the CFU-GM growth for the anthracycline antibiotics and anthracene derivatives. In contrast, for cisplatin and its analogs, there was a better agreement between 1/10 of the peak plasma concentration and the concentration inducing a 10% inhibition of CFU-GM growth. The combination of concentrations inducing inhibitions of 10 and 90% of the CFU-GM growth provides a range of concentrations that predict reasonably well the peak plasma concentrations of several anticancer agents and that could be used as guides for other in vitro investigations.

Anthracenes↗

PubMed1986

Effect of intratracheally administered anticancer drugs on lung hydroxyproline content.

The systemic administration of the anticancer drug bleomycin is associated with the development of lung damage and fibrosis. Intratracheal (i.t.) instillation of bleomycin has often been employed in animal models of this lesion to more rapidly elicit lung damage. However, various drugs and chemicals are known to induce lung damage and fibrosis when given i.t. The results presented here demonstrate that, in addition to bleomycin, the i.t. instillation of dactinomycin, mitomycin c, doxorubicin, and cyclophosphamide resulted in increased lung levels of hydroxyproline, an indicator of fibrosis. In contrast, increases were not seen following i.t. doses of 5-fluorouracil or vincristine, and 1,3-bis(2-chloroethyl)-1-nitrosourea(BCNU) actually decreased lung hydroxyproline content. These findings suggest that i.t. treatments with bleomycin may produce lung damage more representative of anticancer drugs in general than the specific lesion which is produced when bleomycin is administered systemically. The mechanisms underlying i.t. drug-induced increases in lung hydroxyproline are not known, but may be related to the ability of cell-cycle-nonspecific anticancer drugs to directly damage alveolar epithelial cells.

Animals↗