Types Of Anticancer Drugs Research Articles

Specific Regulation of Point-Mutated K-ras-Immortalized Cell Proliferation by a Photodynamic Antisense Strategy

It has been reported that point mutations in genes are responsible for various cancers, and the selective regulation of gene expression is an important factor in developing new types of anticancer drugs. To develop effective drugs for the regulation of point-mutated genes, we focused on photoreactive antisense oligonucleotides. Previously, we reported that photoreactive oligonucleotides containing 2'-O-psoralenylmethoxyethyl adenosine (2'-Ps-eom) showed drastic photoreactivity in a strictly sequence-specific manner. Here, we demonstrated the specific gene regulatory effects of 2'-Ps-eom on [(12)Val]K-ras mutant (GGT --> GTT). Photo-cross-linking between target mRNAs and 2'-Ps-eom was sequence-specific, and the effect was UVA irradiation-dependent. Furthermore, 2'-Ps-eom was able to inhibit K-ras-immortalized cell proliferation (K12V) but not Vco cells that have the wild-type K-ras gene. These results suggest that the 2'-Ps-eom will be a powerful nucleic acid drug to inhibit the expression of disease-causing point mutation genes, and has great therapeutic potential in the treatment of cancer.

In vivo assessment of temozolomide local delivery for lung cancer inhalation therapy

The aim of this study was to compare the efficacy of local drug delivery by inhalation to intravenous delivery in a B16F10 melanoma metastatic lung model. Temozolomide was formulated as a suspension, which was elaborated and evaluated in terms of particle size, shape and agglomeration. An endotracheal administration device was used to aerosolise the suspension. This mode of delivery was evaluated at different temozolomide concentrations and was optimized for the uniformity of delivered dose, the droplet size distribution and the distribution of droplets in vivo. Of the particles in the stabilised suspension, 79% were compatible with the human respirable size range, and this formulation retained 100% in vitro anticancer activity as compared to temozolomide alone in three distinct cancer cell lines. The pulmonary delivery device provided good reproducibility in terms of both the dose delivered and the droplet size distribution. Most of the lung tissues that were exposed to aerosol droplets contained the particles, as revealed by fluorescent microscopy techniques. The global in vivo antitumour activity of the inhaled temozolomide provided a median survival period similar to that for intravenous temozolomide delivery, and three out of 27 mice (11%) survived with almost complete eradication of the lung tumours. The present study thus shows that inhalation of a simple liquid formulation is well tolerated and active against a very biologically aggressive mouse melanoma pulmonary pseudo-metastatic model. This inhalation delivery could be used to deliver other types of anticancer drugs.

Effective Anticancer Drug and Food Choices Based on Polyamine Levels in Cancer Tissues

This review addresses mainly the polyamine levels in various tissues and regional brain of (intact) rats treated with various types of anticancer drugs and those in diverse foods. Results indicate that the most effective combination therapy for cancer patients based on polyamine level is a polyamine-free diet coupled with drugs that reduce the amine in cancer-bearing host tissues. Keywords: Polyamine, anti-cancer drug, food, cancer, rat, human, therapy

CE separation approaches for combinations of anthracyclines and taxanes

For the first time the versatility of CE is demonstrated for the separation of different types of anticancer drugs - anthracyclines and taxanes simultaneously. The use of these drugs in combination therapy for cancer has sparked interest in the development of methods for potential application. The simultaneous analysis of anthracyclines and taxanes can significantly increase a sample throughput of a clinical laboratory. The study shows the potential of CE for such a challenge: anthracyclines and taxanes were separated by CZE, MEKC and MEEKC. The MEEKC method was successfully applied to these compounds for the first time and was characterised by very short separation time, high efficiencies of peaks and was proven to be generic for the separation of different combinations of anthracyclines and taxanes. This separation approach could be highly beneficial for clinical analysis if applied with a sensitive detection system. MEKC and high-speed MEEKC methods were proven to show good potential in their application to plasma samples.

Mitotic checkpoint defects in human cancers and their implications to chemotherapy

The mitotic checkpoint, also known as spindle assembly checkpoint, is to ensure accurate chromosome segregation by inducing mitotic arrest when errors occur in the spindle structure or in the alignment of the chromosomes on the spindle. Loss of mitotic checkpoint control is a common event in human cancer cells, which is thought to be responsible for chromosome instability frequently observed in cancer cells. Several reports have shown that cells with a defective mitotic checkpoint are more resistant to several types of anticancer drugs from microtubule disruptors to DNA damaging agents. In addition, inactivation of key mitotic checkpoint proteins such as BUB (budding uninhibited by benzimidazole) and MAD (mitotic arrest deficient ) is influential in drug resistance in mitotic checkpoint defective cancer cells. The mitotic checkpoint has also been linked to DNA damage response and a defective mitotic checkpoint confers cancer cells resistance to certain DNA damaging anticancer drugs. This review presents recent evidence on mitotic checkpoint defects in human cancers and their association with resistance to anticancer drugs. In addition, the clinical importance and potential therapeutic implications of targeting the mitotic checkpoint to reverse drug resistance in cancer cells are also discussed.

Selective regulation of mutant K-ras mRNA expression by photo-cross-linking antisense oligonucleotide

It has been reported that point mutations in genes are responsible for various cancers and the selective regulation of the gene expression is an important issue to develop new types of anticancer drugs. In this report, we report new types of antisense molecules that photo-cross-link to target mRNA having a point mutation site in a sequence specific manner. We designed and synthesized photo-reactive antisense oligonucleotides containing a 2'-O-psoralen-conjugated adenosine (2'-Ps-oligo). They contain a psoralen via an ethoxymethylene linker (2'-Ps-eom), a propoxymethylene linker (2'-Ps-pom) and a buthoxymethylene linker (2'-Ps-bom), respectively. We evaluated the photo-cross-linking efficiency and the sequence specificity toward complementary RNA. 2'-Ps-eom showed the highest photo-cross-linking efficiency among 2'-Ps-oligos.

First International Meeting on Quadruplex DNA.

On April 21, thousands of visitors invaded Louisville, KY, including >100 scientists from around the globe. Most of the visitors were there to enjoy the festivities that were in progress as a prelude to the Kentucky Derby. In addition to the Derby celebration, the scientists were there for the First International Meeting on Quadruplex DNA, the first-ever full conference on the roles of quadruplex DNA in biology and chemistry. The field is relatively new. It is quite promising for helping scientists understand cancer and perhaps other diseases, and for the development of new types of anticancer drugs. The meeting opened on Saturday evening with a reception on the 16th floor of the historic Brown Hotel in downtown Louisville. The conference attendees had the pleasant choices of catching up with friends, enjoying the food and drink, or gazing through the large windows of the reception area as the world’s largest fireworks display exploded over the nearby Ohio River (Figure 1). The excitement of being part of the first meeting in this area, and the excellent talks in several different quadruplex research areas, held the interest of the conference group until its end at midday on April 24. No heated discussions took place during the conference sessions; however, areas clearly exist in this relatively new field in which significantly different views must be reconciled.

Proteomic profiling of MCF-7 breast cancer cells with chemoresistance to different types of anti-cancer drugs

Chemoresistance is a poor prognostic factor in breast cancer and, thus, presents a significant clinical challenge. The mechanisms of chemoresistance involve multiple complex biological processes. This study aims to identify common contributory factors to chemoresistance in breast cancer by comparing protein expression profiles of chemosensitive MCF-7 breast cancer cells and cells resistant to two different commonly used anti-cancer drugs (adriamycin and paclitaxel). Expression of the ATP binding cassette transporter, P-glycoprotein (P-gp), in breast tumours has previously been found to correlate with poor prognosis in vivo and, accordingly, we confirmed overexpression of P-gp in both adriamycin- and paclitaxel-resistant MCF-7 cells. Using two-dimensional gel electrophoresis and MALDI-TOF peptide mass fingerprinting, we identified 20 proteins differentially expressed between chemosensitive, adriamycin-resistant and paclitaxel-resistant MCF-7 cells. Cytokeratin-8, keratin-19, Hsp-27, 14-3-3 epsilon, annexin-A2 and phosphoglycerate kinase-1 showed altered expression in both adriamycin- and paclitaxel-resistant cells. Validation of a number of these changes was confirmed by Western blotting. Our findings provide further insights into the complex mechanisms of chemoresistance, as well as representing an attractive starting point for the identification of potential protein biomarkers to predict response to chemotherapy in breast cancer in vivo.

Thirty years of polyamine-related approaches to cancer therapy. Retrospect and prospect. Part 1. Selective enzyme inhibitors.

As soon as the natural polyamines (PAs), putrescine (Put), spermidine (Spd) and spermine (Spm), were recognized as ubiquitous constituents of eukaryotic cells, their involvement in growth-related processes attracted particular interest. The high activities of ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC) in rapidly growing tissues and cells, particularly in tumour cells, suggested PA biosynthesis as a target for antineoplastic therapy. In the course of the years selective inhibitors have been developed for literally all enzymes of PA metabolism. Some became important as tools in the elucidation of the PA metabolic system, but only few of them were efficient as inhibitors of tumour growth. A major reason for the inefficacy of selective enzyme inhibitors as anticancer drugs is the sophistication of the system, which regulates intracellular PA pools. Selective blockade of a single enzyme induces changes of metabolism and transport, which compensate for the deficit. The selective impairment of tumour growth is in addition hampered by the ubiquitous occurrence of the PAs, their importance in normal functions of nearly all mammalian cells, and the ability or the mammalian organism to utilize exogenous (gastrointestinal) PAs. Among the inhibitors of PA-related enzymes, the ODC inactivator (R, S)-2-(difluoromethyl)ornithine (DFMO) became most famous. Although it was disappointing in most therapeutic attempts to use it as single drug, it has--based on its low toxicity--considerable potential in cancer chemoprevention, and it turned out to be a highly efficient anti-trypanosome agent. Very likely DFMO is suitable to improve the efficacy of some of the current cytotoxic drugs, and it may allow one to create new therapies in combination with other PA-directed drugs. Some of the less selective enzyme inhibitors, particularly those, which inhibit two or more enzymes of PA metabolism, appear to have had a chance to become practically useful, but they have not been developed energetically. Disregarding DFMO, the AdoMetDC inhibitor SAM486A is the only compound for which clinical trials were published. The future of this drug is unclear at present; presumably phase III clinical trials have been discontinued. One of the lessons that had to be learned from the work on selective enzyme inhibitors was that PA metabolism is a much more difficult target, than has been expected on the basis of the simplicity of the PA structures, and the simple reactions involved in their biosynthesis. In order to inhibit tumour growth several reactions or regulatory functions of PA metabolism have to be impaired at the same time. Recent efforts devoted to the development new types of anticancer drugs, which are based on the perturbation of PA metabolism by structural analogues of the natural PAs, take this message into account. These approaches are the topic of the 2nd part of this overview.

Down-regulation of telomerase activity by anticancer drugs in human ovarian cancer cells.

Maintenance of telomere length is crucial for survival of cells. Telomerase, an enzyme that is responsible for elongation of shortened telomeres, is active in human germ cells as well as most tumor tissues and experimentally immortalized cells. In contrast, most mature somatic cells in human tissues express undetectable or low telomerase activity, implying the existence of a stringent and negative regulatory mechanism. In this study we report the effects of anticancer drugs on telomerase activity in human cancer cells. In assaying for telomerase activity, we basically followed the original TRAP assay system, but with some modifications. A down-regulation of telomerase activity was found when cells of a human ovarian cancer cell line, A2780, were treated with;cis-diamminedichloroplatinum(II) (CDDP; cisplatin). However, down-regulation of telomerase activity was not found in cells of a cisplatin-resistant cell line, A2780CP, treated with cisplatin. On the other hand, telomerase activity in both the cell lines A2780 and A2780CP was reduced when A2780 or A2780CP was treated with adriamycin, an anthracycline antibiotic having a broad spectrum of antineoplastic activity. The different effects on the telomerase activity of the two types of anticancer drugs may be due the distinct chemical functions of these drugs. The present results may indicate a positive relationship between anticancer effects and down-regulation of telomerase activity by anticancer drugs.

Lethal drug interactions of the new antiviral, sorivudine, with anticancer prodrugs of 5-fluorouracil

In 1993 eighteen Japanese patients with cancer and herpes zoster, a viral disease, died from interactions of the new oral antiviral drug, sorivudine (SRV: 1-beta-D-arabinofuranosyl-(E)-5-(2-bromovinyl)uracil), with oral anticancer prodrugs of 5-fluorouracil (5-FU) within 40 d after SRV was approved by the Japanese government and began to be used clinically. Before the death, most of these patients had severe symptoms of toxicity, including diarrhea with bloody flux and marked decreases in white blood cell and platelet counts. All of these patients received SRV daily for several days while being administered long-term anticancer chemotherapy with one of the oral 5-FU prodrugs. There was no acute toxic symptom in patients who received SRV alone or SRV and the other types of anticancer drugs. A toxicokinetic study was carried out using rats to investigate the mechanism of the acute death in the patients caused by drug interactions between SRV and 5-FU prodrugs. Rats were orally coadministered SRV with tegafur (FT: 1-(2-tetrahydrofuryl)-5-fluorouracil), a 5-FU prodrug that most of the patients were considered to receive before the death. All the rats receiving SRV and FT once daily showed extremely elevated levels of 5-FU in the plasma and tissues, including bone marrow and small intestines, and died within 10 d, while the animals given the same repeated dose of SRV or FT alone were still alive over 20 d without any appreciable toxic symptom. Before their death, there were a marked damage of bone marrow, a marked atrophy of intestinal membrane mucosa, marked decreases in white blood cells and platelets, diarrhea with bloody flux, and severe anorexia as reported for the patients. Data obtained by in vivo and in vitro studies indicated that (E)-5-(2-bromovinyl)uracil (BVU), generated from SRV by the gut flora and absorbed through the intestinal membrane, was reduced in the presence of NADPH to a reactive form by hepatic dihydropyrimidine dehydrogenase (DPD), a key enzyme regulating the tissue 5-FU levels from FT, bound covalently to DPD as a suicide inhibitor, and markedly retarded the catabolism of 5-FU. An irreversible inactivation by BVU of rat and human DPDs, expressed in E. coli for the latter, was observed in the presence of NADPH with their purified preparations in a manner reciprocal to radiolabelling of the enzyme proteins with [14C]BVU. SRV showed no inhibitory effect on the rat and human DPDs in the presence of NADPH.

Screening of peptides which suppress the proliferation of transformed cells

We have carried out three rounds of screening tests using 239 synthetic tripeptides for the growth-inhibitory activity toward tumor cells and found that those having amino acid sequences of Pro-Thr-Trp or Glu-Arg-Pro effectively inhibit proliferation of transformed cells. These peptides could be the fundamental structures of new types of anticancer drugs.

Synergistic inhibitory effects of dipyridamole and vincristine on the growth of human leukaemia and lymphoma cell lines.

The effects of combinations of dipyridamole, an effective blocker of the salvage pathway of DNA synthesis, and 8 types of anti-cancer drugs on the growth of human T, B and myeloid leukaemia/lymphoma cell lines in vitro were examined. In combinations, dipyridamole and vincristine (VCR), and dipyridamole and vindesine had synergistic inhibitory effects. Dipyridamole reduced the efflux of VCR from cells and enhanced their VCR accumulation in a dose-dependent manner at concentrations of up to 10 microM in the lymphoid cell lines, MOLT-3 and BL-TH, and of up to at least 20 microM in the myeloid cell line, ML-1. Dipyridamole also enhanced the accumulation of VCR in PHA-stimulated and un-stimulated lymphocytes of normal donors, but efflux of VCR was more rapid from normal lymphocytes than from cultured cell lines. It is proposed that combination therapy with dipyridamole plus VCR should be effective in the treatment of leukaemia and lymphoma.

In vitro and in vivo studies on potentiation of cytotoxic effects of anticancer drugs or cobalt 60 gamma ray by interferon on human neoplastic cells.

A possibility that interferon may potentiate the cytotoxic effects of anticancer drugs or 60Co gamma ray on human neoplastic cells was studied by in vitro and in vivo experimental procedures. The human neoplastic cells used were HeLa (uterine cervical cancer) and WI-38 CT-1 (embryonic lung fibroblasts transformed in culture by 60Co gamma ray) cells. As normal human cells, WI-38 cells were used. Interferon was a preparation of beta-type produced by human fibroblasts. The cytotoxicity was determined by colony formation for in vitro experiments and by tumor growth for animal experiments. Of 17 anticancer drugs, the cytotoxic effects of six drugs, namely, peplomycin, bleomycin, aclacinomycin, cisplatin, 5-fluorouracil (5-FU), and Adriamycin (doxorubicin) were potentiated by concomitant application of interferon. The cytolethal effects of 60Co gamma ray were also enhanced by interferon. The growth of tumor induced by transplantation of HeLa cells into a nude mouse was remarkably reduced by combination therapy of interferon and 5-FU. The current results indicate a possibility that combined therapy of certain types of anticancer drugs or 60Co gamma ray with interferon may be effective in treatment of cancer patients.