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PubMed2003

Anticancer drug resistance of HeLa cells transfected with rat glutathione S-transferase pi gene.

OBJECTIVE: To establish a cytologic expressing system of rat glutathione S-transferase pi (GST-pi) cDNA for detecting the resistance of HeLa cells to anticancer drugs. METHODS: The assessment was made with various anticancer drugs (adriamycin, mitomycin, cisplatinum and vincristine) that showed different cytotoxicities in transfectant HeLa cells with pSV-GT containing rat GST-pi cDNA (HeLa/pSV-GT) or control pSV-neo (HeLa/pSV-neo). Expression levels of GST-pi mRNA in HeLa/pSV-GT and HeLa/pSV-neo were measured by in situ hybridization using Digoxin-labelled cDNA probe. RESULTS: HeLa/pSV-GT expressed significantly high degree of GST-pi mRNA, whereas both HeLa/pSV-neo and HeLa cells had very low expression. Cytotoxicities of HeLa/pSV-GT and HeLa/pSV-neo with 4 anticancer drugs were measured by MTT assay. Drug concentrations for yielding 50% inhibition (IC50) in HeLa/pSV-GT by adriamycin, mitomycin and cisplatinum were 70.13 microg/mL, 10.95 microg/mL and 16.52 microg/mL, respectively. In contrast, IC50 in HeLa/pSV-neo was 10.34 microg/mL, 7.48 microg/mL and 13.70 microg/mL, respectively. The cytotoxicities of vincristine on both HeLa/pSV-GT and HeLa/pSV-neo were not significantly different. CONCLUSIONS: Our findings suggest that HeLa/pSV-GT containing rat GST-pi cDNA is resistant to some anticancer drugs due to overexpression of GST-pi. Also, HeLa/pSV-GT cell line could serve as a useful cytogenetic model for further research.

Animals↗

PubMed1992

[Cell culture and its application--in vitro evaluation of anticancer activity using human tumor cell lines].

Selective toxicity against cancer cells is a most important determinant for anticancer agents. Therefore, we have preferably evaluated anticancer effects in vivo using murine tumor models for several decades. Approximately 50 anticancer agents are currently available for clinical therapy, but very few agents are effective against some types of cancer. Much progresses in cell culture techniques resulted in establishment of various human tumor cell lines. Currently, we are able to use human tumor lines as well as murine ones for the examination of drug sensitivity. A number of assay methods to evaluate anticancer activity have been developed. In the beginning, growth inhibitory activity was evaluated by counting cell numbers after drug exposure. Then, human tumor clonogenic assay (HTCA) was designed to measure only proliferative cells. Recently colorimetric MTT assay and SRB assay in 96-well microplates were developed, which were adopted in the screening system in the NCI, based on a new idea, that is, disease-oriented screening (DOS) using about 60 human tumor cell lines. In this paper outline of each method was described, adding especially several comments on disease-oriented screening.

Antineoplastic Agents↗

PubMed2003

Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA.

Several anticancer drugs target DNA or enzymes acting on the DNA. Because chromatin DNA is tightly compacted, accessibility to the drug target may reduce the efficiency of these anticancer drugs. We thus treated four human cancer cell lines and two normal epithelial cell lines with either trichostatin A (TSA) or SAHA, two histone deacetylase inhibitors, before exposing the cells to VP-16, ellipticine, camptothecin, doxorubicin, cisplatin, 5-fluorouracil, or cyclophosmamide. Pretreatment with TSA or SAHA increased the killing efficiency of VP-16, ellipticine, doxorubicin, and cisplatin. The magnitude of sensitization is cell type specific and is >10-fold for VP-16 in D54, a brain tumor cell line intrinsically resistant to topoisomerase II inhibitors. Topoisomerase II levels and activity were not affected by this treatment, but p53, p21, and Gadd45 protein levels were markedly induced. Moreover, pretreatment with TSA also increased VP-16-induced apoptosis in a p53-dependent and -independent manner. Treating the cells in the reverse order (anticancer drug first, followed by TSA or SAHA) had no more cytotoxic effect than the drug alone. These data suggest that loosening-up the chromatin structure by histone acetylation can increase the efficiency of several anticancer drugs targeting DNA. This may be advantageous for treating tumors intrinsically resistant to these drugs.

Acetylation↗

PubMed2004

[Anticancer drugs off label used of: what do the experts think about?].

Anticancer drugs off label used in Tenon hospital were analysed by a panel of 12 experts not working at Tenon hospital. They distinguished 3 groups of off-label prescribing according to scientific evidence, labelling anticancer drugs alternative in presence and patient's characteristics: justified off label used (62%), unjustified off label used (26%) and prescriptions for which no consensus had been reached between the experts (12%). Nineteen per cent of unjustified off label used had labelling alternative and 7% did not have anticancer drugs labelling alternative. Questions who experts had to answer to analyse drugs prescribing could be systematically asked when a chemotherapy is prescribed. It could allowed to take into account scientific, economic and ethical requirements. This method proposed by the local drug committee could be used to regulate economic resources and to justify financing of some expensive anticancer drugs.

Antineoplastic Agents↗

PubMed2005

50 years of preclinical anticancer drug screening: empirical to target-driven approaches.

The number of anticancer agents that fail in the clinic far outweighs those considered effective, suggesting that the selection procedure for progression of molecules into the clinic requires improvement. The value of any preclinical model will ultimately depend on its ability to accurately predict clinical response. This review focuses on the major contributions of preclinical screening models to anticancer drug development over the past 50 years. Over time, a general transition has been observed from the empirical drug screening of cytotoxic agents against uncharacterized tumor models to the target-orientated drug screening of agents with defined mechanisms of action. New approaches to anticancer drug development involve the molecular characterization of models along with an appreciation of the pharmacodynamic and pharmacokinetic properties of compounds [e.g., the US National Cancer Institute (NCI) in vitro 60-cell line panel, hollow fiber assay, and s.c. xenograft]. Contributions of other potentially more clinically relevant in vivo tumor models including orthotopic, metastatic, and genetically engineered mouse models are also reviewed. Although this review concentrates on the preclinical screening efforts of the NCI, European efforts are not overlooked. Europe has played a key role in the development of new anticancer agents. The two largest academic drug development groups, the European Organisation for Research and Treatment of Cancer and Cancer Research UK, have been collaborating with the NCI in the acquisition and screening of compounds since the 1970s. As with the drug development process internationally, rational pharmacodynamic approaches have more recently been adopted by these two groups.

Animals↗

PubMedDate not supplied

Anticancer compounds and sphingolipid metabolism in the colon.

Sphingomyelin metabolism generates anticancer signals such as ceramide and sphingosine that may inhibit cell proliferation, and induce differentiation and apoptosis. Changes of sphingomyelin metabolism are found to be associated with tumorigenesis in various tissues and a particular link between sphingomyelin metabolism and colon cancer has been indicated. The effects of several anticancer drugs on sphingomyelin metabolism have been examined recently and there is an increasing interest in discovering new drugs taking sphingomyelin as a target. The present review outlines the sphingomyelin metabolism pathway, introduces the evidence linking sphingomyelin to colon cancer, and summarizes the anticancer drugs and dietary factors that affect the metabolism of sphingomyelin and, thus, the production of the anticancer messengers in the colon.

Animals↗

PubMed2005

[Hsp70 chaperone and the prospects of its application in anticancer therapy].

Major stress protein Hsp70 is known to possess two important properties: ATP-dependent activity and protective activity; these two are thought to play a significant role in anticancer therapy. Many malignant tumors contain high amounts of intracellular Hsp70. Moreover, many anticancer drugs themselves are able to elevate Hsp70 expression in tumor cells. Since Hsp70 was found to disturb many signal pathways of apoptosis in many points, the high chaperone expression may lead to an increased resistance of tumor cells to anticancer drugs. On the other hand, when overexpressed by a certain mechanism, Hsp70 is able to emerge at the cell surface by itself or together with tumor antigens and present these to immune cells T-lymphocytes and natural killers, in such a manner that makes cancer cell recognized and abolished. These properties make Hsp70 very promising instrument in designing some novel anticancer vaccines.

Animals↗

PubMed2006

Trichostatin A improves the anticancer activity of low concentrations of curcumin in human leukemia cells.

Curcumin (Cur), a promising anticancer drug, kills tumor cells through either diminishing or promoting reactive oxygen species (ROS) generation. In this study, it was investigated whether trichostatin A (TSA), a specific histone deacetylase (HDAC) inhibitor and a new anticancer drug, could improve the anticancer activity of low concentrations of Cur in human leukemia cells (HL-60). HL-60 cells were treated with Cur, TSA or their combinations; cell proliferation arrest, lactate dehydrogenase (LDH) release and cell viability were measured as indicators of cell damage. Reactive oxygen species (ROS) accumulation and the acetylation of histones were also measured. The cytotoxicity of Cur and TSA increased in a time and dose-dependent manner. Low Cur (no more than 20 microM) diminished the ROS generation in HL-60 cells, while high Cur (50 and 100 microM) promoted that. In contrast, TSA showed no influence on ROS generation. When their effects on histone acetylation were determined, low Cur showed no effect, while TSA significantly increased that. As expected, combinations of low Cur and TSA could not only diminish ROS generation, but also increase histone acetylation, and hence showed a more significant cytotoxicity in HL-60 cells. Since the extra ROS generation may also harm normal cells, instead of using high Cur, combining low Cur with TSA is obviously a better strategy to improve the anticancer activity of Cur.

Acetylation↗

PubMed2006

[Dexrazoxane (ICRF-187)--a cardioprotectant and modulator of action of some anticancer drugs].

The nthracycline antibiotics are among the most widely used and effective anticancer drugs. The therapeutic efficacy of this class of drugs is limited by cumulative cardiac toxicity. Dexrazoxane is the only clinically approved cardioprotective agent used in anthracycline-containing anticancer therapy. Its cardioprotective action allows the use of a much higher cumulative dose of anthracyclines and improvement in the effectiveness of treatment. Anthracyclines form complexes with iron ions, which are very active in the production of reactive oxygen species responsible for the lipid peroxidation of mitochondrial and endoplasmatic reticulum membranes. This process seems to be the major cause of anthracycline-induced cardiotoxicity. Dexrazoxane exerts its protective effects by rapid and complete binding of ferric and ferrous ions, even by displacing the metal ions from complexes with anthracyclines. Besides its cardioprotective effect, dexrazoxane also exhibits anticancer properties. Like other derivatives of bisdioxopiperazine, dexrazoxane is a catalytic inhibitor of eukaryotic DNA topoisomerase II, the key enzyme controlling DNA topology and contributing to the replication and transcription processes. Dexrazoxane is able to lock topoisomerase II at the stage of the enzyme reaction cycle where the enzyme forms a closed clamp around the DNA. This phenomenon seems to be the main reason for the generation of DNA double-strand breaks by dexrazoxane as well as its cytotoxicity against quickly proliferating cancer cells. Other effects of its topoisomerase II catalytic inhibition is the induction of cell differentiation and apoptosis. Dexrazoxane may be used not only as a cardioprotective agent, but also as a modulator of action of some anticancer drugs by enhancing their selectivity or by delaying the development of multidrug resistance.

Anthracyclines↗

PubMed1990

Pharmacokinetics and pharmacodynamics of anticancer agents: contributions to the therapy of childhood cancer.

Strategies for treating pediatric malignancies have not only been successful (i.e., curative) for several disseminated childhood cancers, they have also served as paradigms for the therapy of many adult cancers. Initial strategies included combined treatment modalities (chemotherapy, surgery, radiotherapy) and combinations of different pharmacologic classes of anticancer drugs given in the appropriate schedules. Despite the currently successful therapy for some malignancies (e.g., 70% 4-year disease-free survival in acute lymphocytic leukemia), many children die without known reason. Recent advances in the clinical pharmacology of anticancer drugs have identified relationships between dose intensity and response (efficacy, toxicity). Traditional methods of measuring dose intensity (prescribed dose) have evolved to more sophisticated approaches in maximizing the intensity of treatment, with good response rates. Other methods of optimizing chemotherapy for individual patients include bone marrow support procedures and therapy with biologic response modifiers. Relatively few clinically useful new anticancer drugs have been discovered in the past several years. Fortunately, the potential to improve therapy with currently available agents has come about through enhanced knowledge of the biochemical and clinical pharmacology of anticancer drugs and biologic response modifiers, as well as improved understanding drug resistance biology.

Antineoplastic Agents↗

PubMed1990

[An observation of the anticancer activity of mitoxantrone hydrochloride injection].

Experimental results of anticancer activity of DHAQ.HCl are reported in this paper. It was discovered that DHAQ.HCl, mitoxantrone hydrochloride, had an obvious anticancer effect on the experimental tumor strains:Ehrlich ascites cancer, Sarcoma-180, Leukemia P388, etc., and that it was more effective to Leukemia P388 than to other strains. The anticancer activity of DHAQ.HCl was better than DHAQ (P less than 0.05). No side effect was observed on the local sites (s.c.) of tumor planted or drug injected. And also a good anticancer effect was observed on the sites of tumor planted by local injection. It is suggested that this observation can provide some information on the choice of routes of administration of this drug clinically.

Animals↗

PubMed1985

Potentiation by squalene of the cytotoxicity of anticancer agents against cultured mammalian cells and murine tumor.

Squalene (SQ) was examined for ability to potentiate the cytotoxicity and antitumor activity of anticancer agents. The dose-response curves of cell survival of cultured HeLa or V79 cells in the presence of various anticancer agents [adriamycin (ADM), 5-fluorouracil (5-FU), bleomycin (BLM) and cis-dichlorodiamminoplatinum (CDDP)] showed that SQ potentiated the cytotoxicity of these anticancer agents. SQ may enhance the cytotoxic effect of ADM by interfering with the efflux of ADM from the cells. The antitumor activities of these anticancer agents combined with SQ were tested against sarcoma 180 (S180) ascites cells. Some combinations were found to show synergistic antitumor effects: ADM, BLM or CDDP with SQ was effective against S180, but only slight if any synergistic effect was observed with the combination of 5-FU and SQ. The antitumor activity of BLM was most strongly potentiated by SQ, among the tested agents.

Animals↗

PubMed1985

[Antineoplastic effect of Hu-IFN-beta and other anticancer drugs on malignant brain tumors in athymic nude mice].

We have been studying the therapeutic effect of anticancer drugs such as ACNU and vincristine in human glioma-bearing nude mice models and this time, the effect of interferon was also evaluated. Since 1980, the phase 1, 2 clinical trials on Hu-Interferon (IFN) have been studied in the neurosurgical field and the effect is now regarded to be not as pronounced as previously expected. It is difficult to compare the effect of IFN with other anticancer drugs in an in-vivo study, because of the species specificity of IFN, and only a few studies have so far been reported. With respect to evaluating the therapeutic effect of IFN, the nude mouse model is thought to be useful. The anticancer activity of beta-IFN in nude mice, receiving subcutaneous transplants of human brain tumors (6 strains) was compared with that of conventional anticancer drugs. After 3 weeks of treatment with ACNU, vincristine, bleomycin, mitomycin C, alpha-IFN, beta-IFN, poly ICLC, the tumor reduction rates were evaluated by Battelle's method. Although in 2 out of 6 glioma strains, the tumor reduction rate (treated/control values) treated with beta-IFN was evaluated as effective, the effectiveness of beta-IFN was inferior to that of ACNU and vincristine. Therefore, further studies are indicated to evaluate the efficiency of the drug at higher dosage levels and to determine its tolerance dose. The combined modality treatment such as chemotherapy and radiation are issues that are still to be settled by further studies.

Animals↗

PubMed1988

[A randomized controlled study to compare bladder instillation therapy of anticancer agents and combination therapy with OK-432 injection in prevention of post-TUR recurrence of bladder cancer].

To evaluate the effects of bladder instillation chemotherapy of anticancer agents with OK-432 intradermal injection (group A) in preventing postoperative recurrence of bladder carcinoma, a randomized controlled study with intravesical instillation chemotherapy of anticancer agents (group B) as the reference standard was performed. As the anticancer agents, pepleomycin (PEP) was usually used at a concentration of 30 mg/30 ml physiological saline. OK-432 injection dose was gradually increased from 0.5 KE to 5.0 KE and maintenance dose was decided by local skin reactions. There were no differences in the patient's background factors between group A (22 cases) and group B (17 cases). The no-recurrence rate of bladder carcinoma was similar in the two groups, but the no-recurrence rate for the virgin tumor or the stage T0 cases was higher in group B. On the other hand, the values for the recurrent cases or the stage T1,2 cases was higher in group A. The SU-PS skin reaction as an immunological response was significantly higher in group A. There were no severe side effects derived from anticancer bladder instillation or OK-432 injection.

Administration, Intravesical↗

PubMed1989

Damage to DNA strand and the effects of anticancer drugs.

Cancer chemotherapy is, in a sense, similar to the treatment of infectious disease with antibiotics. The main mechanism of action is on DNA and its precursor, and in the process that anticancer drugs exert the effect on cancer cells, the cells always have abnormal metabolism or destruction of DNA. The main cellular target of most alkylating agents, or anticancer antibiotics is DNA, however, among the anticancer drug newly synthesized, there are some compounds which exert the action on DNA. Quinocarmycin, KT6149, which is a derivative of MMC, YM534, which possesses a platelet agglutinating activity, and MCNU, a nitrosourea compound were studied on the anticancer activity and on damage to DNA strand, and it was found that the lethal effect was deeply concerned with single strand scission of DNA.

Antineoplastic Agents↗

PubMed1988

[Arterial administration of oily anticancer agents dissolved in lipiodol fluid in recurrence of hepatoma after hepatic resection and in metastatic liver cancer].

Oily anticancer agents such as SMANCS dissolved in Lipiodol fluid (Lipiodol) were administered to 18 patients with recurrence of hepatocellular carcinoma after hepatic resection and to 87 patients with metastatic liver cancer. The following results were obtained. i) It was proved and to that Lipiodol worked as a carrier of anticancer drugs and that targeting chemotherapy could be achieved. ii) The serum AFP level and tumor size showed a decrease in 91% and 87% of patients with recurrence of hepatoma, respectively. iii) This method could be applied to extrahepatic metastasis of hepatoma, and anticancer activity was also observed in these lesions. iv) The serum CEA level was decreased in 53 patients (83%) and reduction of tumor size was observed in 32 patients (46%) with metastatic liver cancer. v) In 5 out of 7 tumors resected after arterial injection of oily anticancer agents, necrosis was found histologically in over 95% of the tumor.

Antibiotics, Antineoplastic↗

PubMed1985

Cross-resistance of vinblastine- and taxol-resistant mutants of Chinese hamster ovary cells to other anticancer drugs.

Stable mutants resistant to the anticancer drug vinblastine (VinR mutants) have been isolated after a single selection step from Chinese hamster ovary cells. Of the two types of VinR mutants which are obtained, one class exhibits specific cross-resistance to only some of the microtubule inhibitors. However, the second type of mutants, which is affected in membrane permeability, exhibits cross-resistance to a wide variety of unrelated compounds. Both classes of VinR mutants showed codominant expression in cell hybrids formed between resistant and sensitive cells. The cross-resistance patterns of the VinR mutants and a single-step mutant resistant to the anticancer drug taxol (TaxR mutant) toward various anticancer drugs have been determined. The mutants resistant to both of these drugs showed significantly increased resistance toward aclarubicin, dactinomycin, doxorubicin, bisantrene, bruceantin, chromomycin A3, demecolcine, colchicine, daunorubicin, ellipticine, emetine, ethidium bromide, maytansine, mithramycin, mitoxantrone, nitidine chloride, olivomycin, podophyllotoxin, puromycin, taxol, vinblastine, vincristine, vindesine, teniposide, and etoposide. Interestingly, either one or both of the above mutants exhibited somewhat enhanced sensitivity toward vidarabine, acivicin, bleomycin, cisplatin, cytarabine, alpha-difluoromethyl-ornithine, 5-FU, tegafur, and tiazofurin. For a number of other anticancer drugs which were examined (chlorambucil, mitolactol, IMPY, hexamethylmelamine, hydroxyurea, diglycoaldehyde, methotrexate, mitoguazone, mitomycin, nocodazole, and 6-thioguanine), the level of resistance of these mutants was found to be unaltered. The information regarding cross-resistance and collateral sensitivity patterns of VinR and TaxR mutants should prove to be very useful in the design of drug combinations which could prove more effective in cancer chemotherapy.

Alkaloids↗

PubMed1986

[Treatment of malignant brain tumors with slowly releasing anticancer drug-polymer composites].

The purpose of this study is to present the methodology and results of a clinical trial of local chemotherapy of malignant brain tumors based on slowly-releasing anticancer drug-polymer composites. The slowly releasing drugs were prepared by combining and mutually dispersing anticancer agents with glassified monomers containing 10% polymetacrylic methyl acid and then this compound was frozen at -78 degrees C and exposed to 1 X 10(6) rad of gamma rays from cobalt 60. Thus we prepared a compound of polymers and anticancer agents. We used needle-shaped capsules of this compound. These capsules release the drug very slowly over 40 days. We administered locally to the malignant brain tumors with either slowly releasing mitomycin, slowly releasing adriamycin, slowly releasing ACNU or slowly releasing 5 Fu drugs. The following techniques were employed in implantation these capsules. Implantation into the remaining tumor wall at the time of excision. Implantation into the tumor by CT-guided stereotactic method. We implanted these drugs into tumor of 55 cases, thereafter we conducted both radiation and chemotherapy with ACNU in most patients. This method has the following advantages: It is possible to be employed to different types of anticancer agents. Both dosage and releasing time can be adjusted. It is possible to administer these capsules postoperatively by the stereotactic method. The clinical study consists of 55 patients, 20 cases of anaplastic astrocytoma, 23 cases of glioblastoma multiforme, 5 cases of oligodendroglioma, 3 cases of medulloblastoma and 4 cases of others. Survival rate estimated by Kaplan-Meier method was 47% in glioblastoma at 12 months and 91% in anaplastic astrocytoma at 18 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗