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PubMed2001

Cytochrome P450 CYP1B1 protein expression: a novel mechanism of anticancer drug resistance.

The overexpression of human cytochrome P450 CYP1B1 has been observed in a wide variety of malignant tumours, but the protein is undetectable in normal tissues. A number of cytochrome P450 enzymes are known to metabolise a variety of anticancer drugs, and the consequence of cytochrome P450 metabolism is usually detoxification of the drug, although bioactivation occurs in some cases. In this study, a Chinese hamster ovary cell line expressing human cytochrome P450 CYP1B1 was used to evaluate the cytotoxic profile of several anticancer drugs (docetaxel, paclitaxel, cyclophosphamide, doxorubicin, 5-fluorouracil, cisplatin, and carboplatin) commonly used clinically in the treatment of cancer. The MTT (3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide) assay was used to determine the levels of cytotoxicity. The key finding of this study was that on exposure to docetaxel, a significant decrease in sensitivity towards the cytotoxic effects of docetaxel was observed in the cell line expressing CYP1B1 compared to the parental cell line (P = 0.03). Moreover, this difference in cytotoxicity was reversed by co-incubation of the cells with both docetaxel and the cytochrome P450 CYP1 inhibitor alpha-naphthoflavone. This study is the first to indicate that the presence of CYP1B1 in cells decreases their sensitivity to the cytotoxic effects of a specific anticancer drug.

Animals↗

PubMed2002

Basal levels and patterns of anticancer drug-induced activation of nuclear factor-kappaB (NF-kappaB), and its attenuation by tamoxifen, dexamethasone, and curcumin in carcinoma cells.

Nuclear factor-kappaB (NF-kappaB) has been implicated in the development of drug resistance in cancer cells. We systematically examined the baseline levels of NF-kappaB activity of representative carcinoma cell lines, and the change of NF-kappaB activity in response to a challenge with four major anticancer drugs (doxorubicin, 5-fluorouracil, cisplatin, and paclitaxel). We found that the basal level of NF-kappaB activity was heterogeneous and roughly correlated with drug resistance. When challenged with various drugs, all the cell lines examined responded with a transient activation of NF-kappaB which then declined to basal level despite variation in the concentration of the agent and the timing of the treatment. In contrast to tumor necrosis factor-alpha (TNF-alpha), which activates NF-kappaB in minutes, NF-kappaB activation induced by anticancer drugs usually occurred more than 1hr after stimulation. A gradual increase of total NF-kappaB and its nuclear translocation, and cytoplasmic translocation of nuclear IkappaBalpha and its degradation were involved in this process. In particular, when cells were pretreated with common biologic modulators such as tamoxifen, dexamethasone, and curcumin, the doxorubicin-induced NF-kappaB activation was attenuated significantly. This inhibition may play a role in sensitizing cancer cells to chemotherapeutic drugs. This study has demonstrated that activation of NF-kappaB is a general cellular response to anticancer drugs, and the mechanism of activation appears to be distinct from that induced by TNF-alpha. These observations may have implications for improving the efficacy of systemic chemotherapy for cancer patients.

Active Transport, Cell Nucleus↗

PubMed2002

Use of Chlamydomonas reinhardtii mutants for anticancer drug screening.

We investigated the possibility of utilizing alga cells instead of mammalian cells for the screening of anticancer drugs. The alga cells grow in synthetic media whereas the mammalian cells require complex and more expensive media along with heavy investment and manpower. To assess the validity of this new approach, analysis of growth inhibition by antitumor agents was carried out jointly on a wall-less (cw15) mutant of Chlamydomonas reinhardtii, that obviates the problem of drug uptake, and the murine leukemic cell line L1210, commonly used for anticancer drug screening. The presence of the topoisomerases I and II (approximately 97 and approximately 2 x 170 kDa, respectively) in the nuclear extracts of C. reinhardtii and their possible role as targets of the drugs was also investigated. Concentrated extracts were separated into >100 and <100 kDa fractions and their topoisomerase I and II activities were measured on relaxation of supercoiled plasmid DNA, decatenation of the catenated kinetoplast DNA and cleavage of plasmid DNA. Our results do not show significant difference in growth inhibition by antitumorals between the wall-less mutant of the alga and the murine leukemic cell line L1210. We noted that alga cells were inhibited by antibiotics that target gyrase, a bacterial variant of topoisomerase II which is also found in chloroplasts. At the molecular level, the alga nuclear fractions, >100 and <100 kDa, displayed the same activities as the mammalian enzymes topoisomerases I and II, respectively, and were blocked by the same poisons. We concluded that the wall-less cw15 mutant of C. reinhardtii could advantageously replace mammalian cells in the screening of the anticancer drugs. The alga enzymes could also provide an opportunity to delineate the phylogeny of the topoisomerase superfamily.

Animals↗

PubMed1998

Indirect-response model for the time course of leukopenia with anticancer drugs.

BACKGROUND: Because both the nadir count and the duration of leukopenia after chemotherapy with anticancer drugs are important, a pharmacodynamic model describing the entire time course of leukopenia is valuable. In this study, a pharmacodynamic model was developed to simulate leukopenia. METHODS: The model was developed with the 3-hour infusion data of paclitaxel. A concentration-time curve of paclitaxel for each patient estimated by a 3-compartment pharmacokinetic model was used as input to the model, which had 2 compartments corresponding to leukocytes in bone marrow and peripheral blood, respectively. Differentiation stages of myeloid cells sensitive to anticancer drugs were assumed, and exposure to a drug during their sensitive period as a function of time was used to inhibit the production of leukocytes in bone marrow. The model was validated by fitting the data of 24-hour infusion of paclitaxel or 14-day infusion of etoposide. RESULTS: Successful fitting of the leukopenia after a 3-hour infusion of paclitaxel was achieved. The following parameters were estimated: lag-time, 58 +/- 38 (mean +/- SD) hours before the leukocyte count started to decline; exposure giving 50% inhibition of leukocyte production (IC), 12.1 +/- 6.1 microg x h/mL; and sensitive period, 288 +/- 64 hours. These estimations were within physiologic ranges. In validation, leukopenia after 24-hour infusion of paclitaxel or 14-day infusion of etoposide was also explained by the model. Age was significantly negatively correlated with IC of paclitaxel (P = .039). CONCLUSIONS: This mechanistic model describes the time course of leukopenia and may provide a platform for pharmacodynamic analysis of anticancer drugs.

Adult↗

PubMed2001

Synthesis of some halogen-containing 1,2,4-triazolo-1,3,4-thiadiazines and their antibacterial and anticancer screening studies--part I.

A series of 7-arylidene-6-(2,4-dichloro-5-fluorophenyl)-3-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines (3) were prepared by the condensation of 4-amino-5-mercapto-3-substituted-1,2,4-triazoles (1) and 3-aryl-1-(2,4-dichloro-5-fluorophenyl)-2-bromo-2-propen-1-one (2). An alternative route for the synthesis of the title compound 3 has been described. The newly synthesised compounds were characterised on the basis of N-analyses, IR, 1H NMR and mass spectral data. Some of the newly synthesised compounds were tested for their antibacterial activities against Gram + ve and Gram - ve bacteria. Among the tested compounds 3n showed the highest degree of antibacterial activity against S. aureus and evaluation of the LD50 value of this compound was carried out. Some of the newly synthesised compounds were also screened for their anticancer activities. Among these, compounds 3b, 3g, 3n and 3p are found to be active against NCI-H460 (lung), MCF7 (breast), SF 268 (CNS) in the preliminary anticancer screening studies. Further, 60-cell-line anticancer studies of these compounds were carried out. The results of such studies are discussed in this paper.

Animals↗

PubMed2003

Quinoxaline chemistry. Part 15. 4-[2-Quinoxalylmethylenimino]-benzoylglutamates and -benzoates, 4-[2-quinoxalylmethyl-N-methylamino]-benzoylglutamates as analogues of classical antifolate agents. Synthesis, elucidation of structures and in vitro evaluation of antifolate and anticancer activities.

We report on an extension of our previous discovery of in vitro anticancer activity of trifluoromethylquinoxalines as analogues of classical and non-classical antifolic methotrexate and trimetrexate. In this case a small number of Schiff bases were obtained from the reaction of 2-bromethyl-3-R-6(7)trifluoromethylquinoxaline and ethyl p-aminobenzoylglutamate, ethyl p-aminobenzoate, p-toluidine instead of the expected 4-[2-quinoxalyl]methyl-N-methylanilino derivatives, which in turn formed with N-methylanilino derivatives. The reaction mechanism has been put forward. Structure elucidation of both Schiff bases and N-methylanilino analogues was achieved by a combination of 1H and 13C NMR spectra and hetcor experiments. Compounds 3a, 3b, 3c, 8, 11, 12, 13, Ie were tested in antifolic enzyme assay [Lactobacillus casei (LcTS), Leishmania major (LmTs), human Thymidylate synthase (hTs), human TS, human dihydrofolate reductase (hDHFR)] while compounds 3a, 3b, 3c were tested for anticancer activity. These results seem to indicate that the Schiff bases are somewhat active either as anticancer or as folate inhibitors, while compound Ie was selectively active against hDHFR with an inhibition constant (Ki) of 200 nM with a specificity of about 1000-folds with respect to hTS.

Antineoplastic Agents↗

PubMed1987

Enhanced inhibition of anticancer drugs by human recombinant gamma-interferon for human renal cell carcinoma in vitro.

We studied the inhibitory effect of seven anticancer drugs and alpha-, recombinant beta-, and recombinant gamma-interferons on the in vitro growth of two established human renal cell carcinomas and 16 renal cell carcinomas obtained from patients using monolayer culture and the double-layer soft agar system. Recombinant gamma-interferon was the most effective of three types of interferon. Combined treatment with recombinant gamma-interferon and some anticancer drugs inhibited the cell growth in both cell lines more than treatment with each drug alone. Treatment with recombinant gamma-interferon and cisplatinum or 5-fluorouracil following a 24-hour incubation with the interferon was more effective than when interferon and the drug were given simultaneously. Treatment using doxorubicin, cisplatinum, or vinblastine with recombinant gamma-interferon synergistically inhibited colony formation in 11 of the 16 renal cell carcinomas that showed clonal growth. Our results suggest that treatment with anticancer drugs in combination with recombinant gamma-interferon is effective for renal cell carcinoma.

Antineoplastic Agents↗

PubMed2002

(Aminoethanol)dichloroplatinum(II) complexes: influence of the hydroxyethyl moiety on 5'-GMP and DNA binding, intramolecular stability, the partition coefficient and anticancer activity.

The influence of tethered hydroxyl groups on the binding behavior of the three (aminoethanol)dichloroplatinum complexes, dichloro(N,N'-bis(2-hydroxyethyl)ethylenediamine)-platinum(II) (1), dichloro(N-(2-hydroxyethyl)ethylenediamine)platinum(II) (2) and cis-dichlorobis(2-hydroxyethylamine)platinum(II) (3) towards 5'-GMP and DNA was investigated by 1H NMR and r(b) measurements, respectively. At pH 7.2, the sequence of reactivity with 5'-GMP is 1>2>>3. Complex 3 reacts very slowly with 5'-GMP and DNA and the amount and lifetime of the intermediate 5'-GMP monoadduct are much larger than for 1 and 2. At pH 5.5, the reaction of 3 with 5'-GMP is markedly accelerated and very small amounts of monoadduct are observed, indicating a pH-dependent ability of the pendant hydroxyl group to interact with the platinum moiety. In addition, the effect of the hydroxyethyl functionality on octanol/water partitioning and in vitro anticancer activity was studied. No correlation between lipophilicity and anticancer activity was detected. Furthermore, the lipophilicity and anticancer activity could not be directly correlated to 5'-GMP or DNA binding activity.

Animals↗

PubMed1996

Inhibition of NO synthase induction by an anticancer drug 4'-epi-doxorubicin in rats.

1. Nitric oxide (NO) plays various physiological roles in tumour tissues. Herein, we examined the effects of an anticancer drug 4'-epi-doxorubicin on NO synthase and the related responses in rat thoracic aorta, rat cerebellum and lung homogenates. 2. Treatment with an anticancer drug 4'-epi-doxorubicin in vitro or in vivo had little effect on the relaxation response to acetylcholine or nitroprusside in rat thoracic aorta. 3. Treatment with 4'-epi-doxorubicin in vitro or in vivo did not alter the constitutive NO synthase activity of rat cerebellum ([3H]-citrulline production from [3H]-arginine). 4. After inducible NO synthase had been induced by lipopolysaccharide, 4'-epi-doxorubicin also neither affected the relaxation response to L-arginine in rat thoracic aorta nor the enzyme activity of rat lung. 5. Coincubation with lipopolysaccharide and 4'-epi-doxorubicin in vitro prevented the development of relaxation response to L-arginine in rat thoracic aorta. Pretreatment with 4'-epi-doxorubicin in vivo also prevented the induction of inducible NO synthase by lipopolysaccharide in rat thoracic aorta and lung. 6. These results suggest that 4'-epi-doxorubicin selectively inhibits the induction of NO synthase without affecting constitutive and inducible NO synthase activities. This effect was discussed in relation to the anticancer and side effects of the drug.

Acetylcholine↗

PubMed2003

Statins may potentiate bisphosphonates anticancer properties: a new pharmacological approach?

Both statins and bisphosphonates may inhibit cancer proliferation by two main different mechanisms: inducing apoptosis along cholesterol synthesis pathway and by antiangiogenic properties. Moreover, also an immunomediated mechanism could be involved in anticancer properties of these molecules. The association of these two drugs could represent an interesting pharmacological approach in anticancer treatment. The available data offer the rationale for future in vitro studies aimed at evaluating proapoptotic and antiangiogenic action of this association. If the results of vitro studies should confirm the hypothesis that statins potentiate the action of bisphosphonates, further clinical investigations could be mandatory to evaluate the efficacy of this new pharmacological approach in anticancer therapy.

Angiogenesis Inhibitors↗

PubMed1997

Disruptions of the hypothalamo-pituitary-adrenal axis increase anticancer drug lethality in the rat.

We have previously shown that toxicity of the anticancer agent hydroxyurea (HU) in the rat is markedly increased by hypophysectomy or adrenalectomy. In this study, we investigated whether increased toxicity in ablated animals is a unique feature of HU or it is shared with other anticancer agents; the toxic effects of five such drugs have been compared in intact, hypophysectomized (HYX) and adrenalectomized (ADX) rats. Bis-chloroethyl-nitrosourea (BCNU, 5-10 mg/kg), busulfan (0.1-10 mg/kg), cyclophosphamide (25-125 mg/kg), 5-fluorouracil (15-75 mg/kg) and vindesine (0.1-0.5 mg/kg) were given to intact and endocrine-ablated rats, and lethality was recorded over 3 weeks. It was found that mortality was low or absent in intact rats, whereas (with the exception of HYX rats receiving the highest dose of busulfan) it was dramatically increased by both hypophysectomy and adrenalectomy. However, replacement treatments with long-acting tetracosactrin and corticosterone to HYX and ADX rats respectively afforded significant protection against BCNU toxicity only. We conclude that the integrity of the hypothalamo-pituitary-adrenal axis is needed to tolerate the toxicity of various anticancer drugs, although complex mechanisms appear to underlie such protective effect.

Adrenalectomy↗

PubMed2000

Enhanced apoptosis of squamous cell carcinoma cells by interleukin-2-activated cytotoxic lymphocytes combined with radiation and anticancer drugs.

Induction of potent apoptosis is required in cancer therapy. We examined the combination effect of interleukin-2-activated lymphocytes (LAK cells) and anticancer drugs or gamma (gamma)-rays on the induction of apoptosis in an established oral squamous cell carcinoma cell line (OSC-3 cells). By pretreatment of OSC-3 cells with (137)Cs (5 Gy), 5-fluorouracil (5-FU) (0.5 microg/ml) or cis-dichlorodiammine-platinum (CDDP) (5 microg/ml), the activation of bid and caspase-3 by LAK cells was strongly increased and associated with an enhanced degradation of poly-(ADP-ribose) polymerase (PARP) and/or nuclear mitotic apparatus protein (NuMA) and the increased fragmentation of DNA. The LAK cell-enhanced caspase-3 activity in the pretreated OSC-3 cells was decreased to approximately 70% and 40% of the control by the addition of Z-AAD-CMK (a granzyme B inhibitor) and neutralising monoclonal antibody to Fas antigen (alphaFas-IgG), respectively. The combined treatment-induced DNA fragmentation was suppressed by approximately 20% and 30% of the control by the addition of Z-AAD-CMK and alpha Fas-IgG, respectively, in the co-culture system. While Ac-DEVD-CHO (a caspase-3 inhibitor) suppressed the DNA fragmentation levels to approximately half and this was similar to the amount of suppression that was obtained by the addition of both alpha Fas-IgG and Z-AAD-CMK. In addition, LAK cell-activated bid may have increased the intracellular reactive oxygen intermediates (ROI) level and induced a decrease of mitochondrial membrane potential. These influences by LAK cells were enhanced when OSC-3 cells were pretreated with each anticancer drug or (137)Cs. Furthermore, the increase of ROI by LAK cells was suppressed by alpha Fas-IgG and Z-AAD-CMK to approximately half the level of the control. These results indicate that anticancer drugs and gamma-rays prime squamous cell carcinoma cells to be susceptible to apoptosis by LAK cells, that LAK cell-induced apoptosis largely depends on the activation of caspase-3 by the Fas/Fas-ligand signal and granzyme B, and that LAK cells induce ROI in the target cells, which is largely mediated by Fas and granzyme B.

Antineoplastic Agents↗

PubMed2002

Downregulation of survivin expression by induction of the effector cell protease receptor-1 reduces tumor growth potential and results in an increased sensitivity to anticancer agents in human colon cancer.

Survivin, a novel inhibitor of apoptosis, is expressed in cancer cells and not in normal adult tissues, and is recognised as a potential target in anticancer therapy. The induction of a natural antisense of survivin, effector cell protease receptor-1 (EPR-1), in a human colon cancer cell line resulted in a downregulation of survivin expression, with a similar decrease in cell proliferation, an increase in apoptosis and an increase in the sensitivity to anticancer agents. In addition, subcutaneous (s.c.) tumours from EPR-1 transfectants showed a significant reduction in size compared with parental cells, and this antitumour efficacy was further enhanced in combination with anticancer agents. These findings suggest that regulation of survivin by the induction of EPR-1 cDNA may have significant potential as a therapy for human colon cancer.

Animals↗

PubMed2002

Synthesis and evaluation of anticancer benzoxazoles and benzimidazoles related to UK-1.

UK-1 is a structurally unique bis(benzoxazole) natural product isolated from a strain of Streptomyces. UK-1 has been reported to possess anticancer activity but no activity against bacteria, yeast, or fungi. Previous work has also demonstrated the ability of UK-1 to bind a variety of di- and tri-valent metal ions, particularly Mg(2+) ions, and to form complexes with double-stranded DNA in the presence of Mg(2+) ions. Here we report the activity of UK-1 against a wide range of human cancer cell lines. UK-1 displays a wide spectrum of potent anticancer activity against leukemia, lymphoma, and certain solid tumor-derived cell lines, with IC(50) values as low as 20 nM, but is inactive against Staphylococcus aureus, a methicillin-resistant strain of S. aureus, or Pseudomonas aeruginosa. A series of analogues of the bis(benzoxazole) natural product UK-1 in which the carbomethoxy-substituted benzoxazole ring of the natural product was modified were prepared and evaluated for their anticancer and antibacterial properties. An analogue of UK-1 in which the carbomethoxy-substituted benzoxazole ring was replaced with a carbomethoxy-substituted benzimidazole ring was inactive against human cancer cell lines and the two strains of S. aureus. In contrast, a simplified analogue in which the carbomethoxy-substituted benzoxazole ring was replaced with a carbomethoxy group was almost as active as UK-1 against the four cancer cell lines examined but lacked activity against S. aureus. Metal ion binding studies of these analogues demonstrate that they both bind Zn(2+) and Ca(2+) ions about as well as UK-1. The non-cytotoxic benzimidazole UK-1 analogue binds Mg(2+) ions 50-fold weaker than UK-1, whereas the simple benzoxazole analogue binds Mg(2+) ions nearly as well as UK-1. These results support a role of Mg(2+) ion binding in the selective cytotoxicity of UK-1 and provide a minimal pharmacophore for the selective cytotoxic activity of the natural product.

Anti-Bacterial Agents↗

PubMed1998

Nucleoside transport and its significance for anticancer drug resistance.

This article discusses the role of nucleoside transport processes in the cytotoxicity of clinically important anticancer nucleosides. This article summarizes recent advances in the molecular biology of nucleoside transport proteins, review the current state of knowledge of the transportability of therapeutically useful anticancer nucleosides, and provide an overview of the role of nucleoside transport deficiency as a mechanism of resistance to nucleoside cytotoxicity are summarized. Several strategies for utilization of nucleoside transport processes to improve the therapeutic index of anticancer therapies, including the use of nucleoside-transport inhibitors to modulate toxicity of both nucleoside and non-nucleoside antimetabolite drugs are also presented.

Journal Article↗

PubMed2002

Expression of P-glycoprotein in rat hepatocarcinogenesis by diethylnitrosamine and the modulation by anticancer drugs.

P-glycoprotein (P-GP) is known to be a multidrug resistant 1 gene product and to exhibit resistance to a broad range of drugs including anticancer drugs such as epirubicin. Its overexpression is reported in human hepatocellular carcinoma and in adenomatous hyperplasia of the liver as well. In order to clarify the evolution of P-GP expression during hepatocarcinogenesis and its modulation by anticancer drugs, we performed an immunohistochemical study in male Wistar rat livers exposed to diethylnitrosamine (DEN) for 12 weeks. Some rats were pretreated with cisplatin or epirubicin 1 week prior to the exposure, and some rats were treated with them at the 10th week after the exposure. While there was no P-GP expression in the liver of the control, cisplatin, and epirubicin (DEN-free) rats, expression was confirmed in the hepatocytes of DEN-treated rats. The immunostaining of hyperplastic nodules was significantly more intense than in well-differentiated hepatocellular carcinomas, and no staining was observed in poorly-differentiated carcinomas. Markedly intense staining was observed in the early hyperplastic nodules of cisplatin-pretreated rats, as well as in epirubicin-pretreated rats. Plasma alpha-fetoprotein levels were markedly elevated in DEN-treated rats, while tumor necrosis factor-alpha levels were not. In conclusion, the results suggest that P-GP confers a protective effect against anticancer drugs and provides a great advantage to the initiated cells. Furthermore, in addition to epirubicin, cisplatin also promotes the induction of P-GP in the initiated cell.

Journal Article↗

PubMed2001

Marine organisms as a source of new anticancer agents.

Various active anticancer agents are derived from plants and terrestrial microorganisms. The isolation of C-nucleosides from the Caribbean sponge, Cryptotheca crypta, four decades ago, provided the basis for the synthesis of cytarabine, the first marine-derived anticancer agent to be developed for clinical use. Cytarabine is currently used in the routine treatment of patients with leukaemia and lymphoma. Gemcitabine, one of its fluorinated derivatives, has also been approved for use in patients with pancreatic, breast, bladder, and non-small-cell lung cancer. Over the past decade, several new experimental anticancer agents derived from marine sources have entered preclinical and clinical trials. This field has expanded significantly as a result of improvements in the technology of deep-sea collection, extraction, and large-scale production through aquaculture and synthesis. In this paper, examples of marine-derived experimental agents that are currently undergoing preclinical and early clinical evaluation are briefly discussed. A summary of the available information on the results of phase I and II trials of agents such as aplidine, ecteinascidin-734 (ET-734), dolastatin 10 and bryostatin 1 is also presented.

Animals↗

PubMed2000

Anticancer properties of bovine milk.

Improved means of cancer prevention and treatment remain key goals of global health programmes. This is particularly true in Western society, where the elderly represent a large proportion of the population, and where the likelihood of tumour development is compounded by risk factors such as poor fibre/high fat diets and environmental pollution. Dietary intervention represents an attractive, non-invasive means of providing anticancer preventative and therapeutic benefits to at-risk individuals. This review focuses on the evidence for anticancer properties of bovine milk and milk-derived components. Evidence of a role for whole milk constituents, as well as purified minor components, in combating tumorigenesis is outlined. Shortcomings in current studies are highlighted, and future opportunities for targeted research to characterize important anticancer properties of milk are discussed.

Animals↗