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PubMed2001

The MRP family and anticancer drug metabolism.

Acquirement of drug resistance by tumor cells is a major chemotherapeutic problem. It is well known that typical multidrug resistance is caused by P-glycoprotein and multidrug resistance related protein (MRP1) which belong to the ATP binding cassette (ABC) transporter family. Ishikawa proposed that the ATP-dependent glutathione-S-conjugate export pump (GS-X pump) and phase III detoxification system are essential to drug metabolism, and this constituted a new concept in drug metabolism and the detoxification of xenobiotics. The GS-X pump has been revealed to belong to the ABC transporter family and suggested to the contribution to anticancer drug resistance. The GS-X pump actively effluxes the glutathione S-platinum (GS-Pt) complex. We cloned novel ABC transporter cDNA from the PC-14/CDDP cell line, and the cloned cDNA was designated as a short-type MRP homologue, SMRP. Further investigation suggested that SMRP is a splicing variant of MRP5. The MRP5 mRNA levels in tumors from lung cancer patients treated with platinum regimen were significantly higher than in tumors from patients treated with non-platinum regimens, and the MRP5 expression levels were correlate with the GCS expression levels that is the rate-limiting step enzyme in glutathione biosynthesis. These results suggested that MRP5 take part in the function of GS-X pump. Recently many transporter molecules belong to the ABC transporter family such as MRP family have been identified, and appear to express in various human tissues. It can be presumed that their molecules are affected by the disposition and metabolism of drugs, but their substrates are still unclear. If the substrate specificity is revealed in the future, it is expected that the anticancer agents transporter, moreover anti cancer drug resistance mechanisms, can be clarified. This review is cited in the cisplatin resistance and the GS-X pump, and finally describes an overview of the MRPs substrates recently clarified, mainly about anticancer drugs.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2002

Analysis of anticancer drugs and their metabolites by mass spectrometry.

There is an increasing awareness that the metabolites of anticancer drugs can contribute to the pharmacodynamic effects that are observed, which has stimulated a much greater emphasis on metabolic and pharmacokinetic issues. This has coincided with the development of electrospray and related atmospheric pressure ionization mass spectrometry techniques such as ionspray (nebulizer assisted electrospray), turboionspray (heated nebulizer assisted electrospray) and atmospheric pressure chemical ionization (nebulization coupled with corona discharge). The combination of collision induced dissociation and tandem mass spectrometry coupled with a soft ionization process that produces abundant molecular species provides very powerful methodology for the trace analysis of drugs and their metabolites. The present review has emphasized the more rigorous quantitative applications that have appeared in the literature over the last five years. It is evident that modern techniques of liquid chromatography tandem mass spectrometry coupled with stable isotope dilution methodology have had a profound effect on our ability to analyze anticancer drugs and their metabolites. As new drugs emerge into the clinic, this methodology will clearly be the method of choice, particularly when many samples have to be analyzed over a short time. This approach was beautifully demonstrated in the study of the novel signal transduction inhibitor, Gleevec where thousands of clinical samples were analyzed for drug and metabolites over a relatively short period of time. The need to analyze anticancer drugs and their metabolites with such prompt turn around times has stimulated even more rapid approaches to analysis using robotic-based purification methodology and short LC chromatographic run times.

Animals↗

PubMed2002

Identifying molecular targets mediating the anticancer activity of histone deacetylase inhibitors: a work in progress.

The anticancer properties of histone deacetylase inhibitors have been known for some time. However, it is only recently that the functional identities of the intracellular targets mediating the anticancer properties have started to be revealed. These targets appear to play significant roles in cell cycle control, apoptosis and differentiation. Importantly, the modulation of these activities is likely to be mediated by alterations in the acetylation status of both histone and non-histone targets. Identification of these targets, and the specific histone deacetylase enzymes that modulate them, is an important step in designing rational-based therapies for the treatment of cancer. In this review we discuss the state of progress in identifying the molecular pathways/events mediating the anticancer activity of histone deacetylase inhibitors.

Animals↗

PubMed2003

The quinolone family: from antibacterial to anticancer agents.

The present review focuses on the structural modifications responsible for the transformation of an antibacterial into an anticancer agent. Indeed, a distinctive feature of drugs based on the quinolone structure is their remarkable ability to target different type II topoisomerase enzymes. In particular, some congeners of this drug family display high activity not only against bacterial topoisomerases, but also against eukaryotic topoisomerases and are toxic to cultured mammalian cells and in vivo tumor models. Hence, these cytotoxic quinolones represent an exploitable source of new anticancer agents, which might also help addressing side-toxicity and resistance phenomena. Their ability to bind metal ion co-factors represents an additional means of modulating their pharmacological response(s). Moreover, quinolones link antibacterial and anticancer chemotherapy together and provide an opportunity to clarify drug mechanism across divergent species.

Anti-Bacterial Agents↗

PubMed2005

Novel anticancer targets and drug discovery in post genomic age.

Cancer is a serious disease with a complex pathogenesis, which threats human life greatly. Currently, great efforts have been put to the identification of novel anticancer targets and the discovery of anticancer drugs following the progress of chemogenomics, which will be reviewed briefly in this article. Furthermore, during the past 5 years, the global effort of sequencing human genome has provided us with an enormous number of potential targets associated with cancer therapy. As a result, the New Drug Discovery (NDD) is undergoing a transition "from gene to drug". Accordingly, the targets for anticancer drugs studies now are focused on some biological macromolecular targets associated with cancer and several interactive mechanisms involved in the growth and metastasis of cancer cells as well as tumor angiogenesis, such as Matrix Metalloproteinases (MMPs), Aminopeptidase N (APN), Tyrosine Kinase (TK), Farnesyltransferase (FTase) and cell Signal Transduction Pathway and so forth. Among these targets the MMP-2, -9 and APN are the most extensively studied enzymes in our laboratory. The peptidomimetics Matrix Metalloproteinase Inhibitors (MMPIs) and APN inhibitors (APNIs) with the molecular scaffold of pyrrolidine, 3-amino-2-hydroxy-4-phenyl butyric acid (AHPA) and glutamylide, which have been designed and synthesized in our laboratory, will be described in the review, among which the pyrrolidine scaffold is patented with the IC(50) ranging from 1 nM to 300 nM against MMP-2, and MMP-9.

Alkyl and Aryl Transferases↗

PubMed2005

Lanthanides as anticancer agents.

The application of inorganic chemistry to medicine is a rapidly developing field, and novel therapeutic and diagnostic metals and metal complexes are now having an impact on medical practice. Advances in biocoordination chemistry are crucial for improving the design of compounds to reduce toxic side effects and understand their mechanisms of action. A lot of metal-based drugs are widely used in the treatment of cancer. The clinical success of cisplatin and other platinum complexes is limited by significant side effects acquired or intrinsic resistance. Therefore, much attention has focused on designing new coordination compounds with improved pharmacological properties and a broader range of antitumor activity. Strategies for developing new anticancer agents include the incorporation of carrier groups that can target tumor cells with high specificity. Also of interest is to develop complexes that bind to DNA in a fundamentally different manner than cisplatin, in an attempt to overcome the resistance pathways that have evolved to eliminate the drug. This review focuses on recent advances in developing lanthanide anticancer agents with an emphasis on lanthanide coordination complexes. These complexes may provide a broader spectrum of antitumor activity. They were compared with classical platinum anticancer drugs. Lanthanides are also of interest because of their therapeutic radioisotopes. The dominant pharmacological applications of lanthanides are as agents in radioimmunotherapy and photodynamic therapy.

Animals↗

PubMed2004

Recent studies on natural products as anticancer agents.

Cancer will be the major cause of death in the 21st century and natural products should provide novel and more effective anticancer agents. This review deals with new natural molecules liable to become anticancer drugs, as well as recent specific strategies for a selective treatment of cancer. The introduction presents the current state of the art on anticancer research. Beside, in the following subheadings we summarize our research on cytotoxic natural quinone methide-triperpenes and their analogues. We also discuss our results on the anti-tumour promoting activity of natural naphthoquinones and their derivatives.

Animals↗

PubMed2005

Recent advances in the new generation taxane anticancer agents.

Recent advances in the design and preclinical evaluations of promising new generation taxane anticancer agents are reviewed in this article. Paclitaxel and docetaxel are two of the most important anticancer drugs today. However, recent reports have shown that treatment with these drugs often encounters undesirable side effects as well as drug resistance. Therefore, it is important to develop new taxane anticancer agents with fewer side effects, superior pharmacological properties, and improved activity against drug-resistant human cancers. Structure-activity relationship (SAR) studies led to the discovery of a series of highly active second-generation taxanes. One of them, "Ortataxel" (SB-T-101131, IDN5109, BAY59-8862), exhibits excellent activity against a variety of drug-sensitive and drug-resistant cancer cell lines, as well as human tumor xenografts in mice. It is orally active and is currently in phase II clinical trials. Photoaffinity labeling of microtubules and P-glycoprotein using photoreactive radiolabeled taxoids has disclosed the drug-binding domain of tubulin as well as Pgp. Together with information on microtubule-bound fluorine-labeled taxoids obtained by solid-state NMR studies, the bioactive conformation of paclitaxel and taxoids appears to emerge. Novel taxane-monoclonal antibody (mAb) immunoconjugates, have shown highly promising results for the tumor-specific delivery and release of an extremely cytotoxic, second-generation taxane. Also, another novel series of second generation taxanes conjugated with n-3 polyunsaturated fatty acids, e.g. decosahexaenoic acid (DHA), has exhibited impressive antitumor activity with minimum general toxicity against the highly drug-resistant DLD-1 human colon cancer xenografts in SCID mice.

Animals↗

PubMed2006

Medicinal chemistry of probimane and MST-16: comparison of anticancer effects between bisdioxopiperazines.

Bisdioxopiperazines, including ICRF-154 and razoxane (ICRF-159, Raz), are a family of anticancer agents developed in the UK, specifically targeting neoplastic metastases. Two other bisdioxopiperazine derivatives, probimane (Pro) and MST-16, were synthesized at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. In order to determine the similarities and differences between these agents in medical chemistry, we evaluated the anti-tumor and anti-metastatic effects of Pro and MST-16 in vitro and in vivo against a number of human tumor cell lines and one of murine origin (Lewis lung carcinoma, LLC), and one human tumor xenograft (LAX-83) in nude mice. Our results show that Pro was cytotoxic to human tumor cell lines in vitro (IC50 < 50 microM for 48 h), approximately 3 to 20-fold more than MST-16. Pro and MST-16 manifested more prolonged cytotoxicity than some other first-line anticancer drugs including 5-fluorouacil, vincristine and doxorubicin, and maintain their cytotoxic effects for 4 days in vitro. In animal experiments, Pro and Raz were active against primary tumor growth (35-50 %) and significantly inhibited pulmonary metastasis of LLC (inhibition > 90 %) at dosage below LD(5). Both Raz and Pro were effective in administration schedules of 1, 5 and 9 days. Both Raz (25-32 %) and Pro (55-60 %) caused statistically significant inhibition of the growth of LAX 83 (a human lung adeno-carcinoma xenograft) in nude mice. In this model, Pro was more effective against LAX83 than Raz at equitoxic dosages. These findings suggest that Pro is active against more categories of tumors both in vivo and in vitro, which in some circumstances may make it superior to the currently-used anticancer bisdioxopiperazines, including razoxane and MST-16.

Animals↗

PubMed2006

Relationships between genetic polymorphisms and anticancer drug cytotoxicity vis-à-vis the NCI-60 panel.

INTRODUCTION: The National Cancer Institute (NCI)-60 panel consists of 60 human tumor cell lines initially established for screening thousands of molecules for antiproliferative activity. It has been powerful for deciphering the relationships between anticancer drug cytotoxicity and cell molecular characteristics. We tested its potential interest for establishing relationships between the polymorphism of genes involved in drug metabolism and transport or in DNA repair, and drug cytotoxicity extracted from NCI databases. METHODS: Using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) techniques, three frequent single nucleotide polymorphisms (SNPs) were analyzed: Lys751Gln in the Xeroderma pigmentosum complementation group D (XPD, ERCC2) gene, Asp1104His in the Xeroderma pigmentosum complementation group G (XPG, ERCC5) gene and Ile105Val in the glutathione S-transferase P1 (GSTP1) gene. RESULTS: The allelic frequencies of the variants were 33% for ERCC2, 23% for ERCC5 and 39% for GSTP1. The ERCC2 polymorphism appeared to be a strong determinant of the in vitro cytotoxicity of most anticancer agents, with lower half maximal inhibitory concentration (IC50) values in variant homozygous lines than in common homozygous or heterozygous cell lines. Unexpectedly, the cytotoxicity of taxanes appeared markedly dependent upon the ERCC2 genotype, with threefold lower mean IC50 values in variant homozygous cell lines. The ERCC5 genotype appeared to be important only for taxanes, with fourfold higher IC50 values in variant homozygous cell lines. The GSTP1 polymorphism was related to the cytotoxicity of several drug classes, especially topoisomerase inhibitors, antimetabolites and N7 alkylating agents. CONCLUSION: The NCI-60 panel is capable of providing clues and tracks for the establishment of clinically useful relationships between a given genotype and the cytotoxicity of an anticancer agent.

Antineoplastic Agents↗

PubMed2005

HSP90: a rising star on the horizon of anticancer targets.

Over the past decade, heat-shock protein (HSP)90 has begun to draw increasing attention as a novel anticancer target with unique features. As a molecular chaperone, HSP90 promotes the maturation and maintains the stability of a large number of conformationally labile client proteins, most of which are involved in biologic processes that are often deranged within tumor cells, such as signal transduction, cell-cycle progression and apoptosis. As a result, and in contrast to other molecular targeted therapeutics, inhibitors of HSP90 achieve their promising anticancer activity through simultaneous disruption of many oncogenic substrates within cancer cells. This review provides a brief summary of HSP90 biology and its association with cancer. It describes the discovery and development of HSP90 inhibitors as anticancer agents and their current status in the clinic. Finally, it closes with a discussion of the unique challenges confronting the further development of these agents and their prospects for the future.

Animals↗

PubMed2000

Anticancer drugs induce apoptosis in mouse hair follicles.

Apoptosis represents an important mode of cell death induced by chemotherapeutic drugs. It is plausible that apoptosis may also play an important role in alopecia caused by anticancer drugs. C57 BL/6 mice were induced to enter into anagen by hair shaft depilation and a single intraperitoneal injection of cyclophosphamide (150 mg/kg) was given. Skin specimens were taken from the backs of mice at day 9, 10, 11, 12 and 13 postdepilation (p.d.). Specimens were stained with TUNEL method, and DNA was isolated from the plucked hair follicles and was electrophoresed. Many TUNEL-positive cells were observed in hair bulbs in the cyclophosphamide group at days 10-13. At day 13 p.d., most follicles were damaged and extensive hair loss was observed. Fragmented DNA, but not so distinct, were observed in a DNA ladder pattern corresponding to the in situ results. This study suggests that anticancer drugs can induce apoptosis-related damage to the hair follicles in mice. Control mice when treated with saline also showed apoptosis when they spontaneously entered into catagen, but they never showed hair loss. Consequently, hair loss induced by anticancer drugs may result from a wave of induced apoptotic death.

Animals↗

PubMed1997

A p53 growth arrest protects fibroblasts from anticancer agents.

Reversible inhibitors of the cell cycle such as the TGF-betas have been exploited to protect dividing cells from exposure to anticancer drugs and radiation. Here, rat embryo fibroblast (REF) lines expressing different p53 mutations were used to test whether the p53 growth arrest could also chemoprotect cells from high doses of anticancer drugs. Whereas the doubling times of the different REF lines at 37 degrees C were similar, cells bearing temperature-sensitive mutations (mouse 135V or human 143A) were growth arrested at 31 degrees C. Temperature-dependent p53 activity was associated with increased levels of MDM2 and p21/WAF1, and the induction of an integrated p53-responsive luciferase gene. The REF lines exhibited similar sensitivities to common anticancer drugs when grown at 37 degrees C. However, when exposed to the same agents following transient incubation at 31 degrees C, the p53-arrested cells exhibited a marked survival advantage as shown by colony-forming assays. Chemoprotection was not universal, in that colony formation was not enhanced significantly after treatment with cisplatin or 5-fluorouracil, two drugs which can cause cellular damage throughout the cell cycle. Like other negative growth regulators, an activated p53 checkpoint may mediate the survival of cells exposed to drugs that target DNA synthesis or mitosis.

Animals↗

PubMedDate not supplied

Rationale for use of local hyperthermia with radiation therapy and selected anticancer drugs in locally advanced human malignancies.

The addition of local hyperthermia to radiation therapy has significantly improved the ability of oncologists to control superficial malignancies. Large tumours, tumours which cannot be heated adequately, and those situated in areas where surrounding normal tissues have decreased radiation tolerance, however, are difficult to eradicate even with this combination treatment. We believe that properly selected and scheduled anticancer drugs will add substantially to the efficacy of local hyperthermia and radiation. A review of the literature concerning the cytotoxic interactions of various anticancer agents with hyperthermia, with radiation and with relevant physiological parameters is presented. From this review, anticancer drugs which are good candidates for trimodality therapy are identified and a general approach to trimodality scheduling is suggested.

Animals↗

PubMed1994

One bead, one chemical compound: use of the selectide process for anticancer drug discovery.

A technology for chemical synthesis and testing of libraries of millions of chemical entities has been developed for rapid molecular and cellular screening for drug leads. Each individual compound in the library is on a separate resin bead. Screening for binding activity can be conducted directly on the beads. Biological activity is assessed in solution phase assay by cleaving a portion of the compound from each bead. The molecular structure of the compound of interest is obtained by automated peptide sequencing from the bead of origin. We have applied this technology to anticancer drug discovery as well as to other pharmaceutical targets. For anticancer drug development, current molecular targets include B-cell lymphoma, the EGF receptor, and the HER2-neu receptor. Solution phase screening with dual cleavable libraries is being used for growth inhibition of human tumor cell lines. Initial in vitro leads have been identified in each of these areas of anticancer drug discovery.

Antibodies, Monoclonal↗

PubMed1987

Interplay between the toxic effects of anticancer drugs and host antitumor immunity in cancer therapy.

The results accumulated thus far illustrate that the therapeutic efficacy of many anticancer drugs depends not only on the direct tumoricidal/tumoristatic activity of the drug but also on the contribution to tumor eradication of antitumor immunity which emerges after the chemotherapy. When a low dose of anticancer drug is employed, it reduces the tumor burden to a lesser extent than a high dose of drug. Consequently, in order for the low dose of drug to be as effective as a high dose of drug, antitumor immunity has to control a larger tumor burden than that controlled by the immune system following high-dose chemotherapy. This was shown to happen in several experimental tumor models wherein the low dose of drug greatly potentiated host antitumor immunity while the high dose of drug either potentiated host antitumor immunity to a lesser extent, did not potentiate it at all, or actually exerted a suppressive effect on host antitumor immunity. As a result of the immunopotentiating activity of the low dose of drug, tumor-bearing animals which did not exhibit concomitant antitumor immunity due to the inhibitory activity of suppressor cells, developed a very potent antitumor immunity shortly after the chemotherapy. The immunopotentiating effect of the low dose of drug was attributed in these situations to drug-mediated selective elimination of suppressor cell activity and possibly also to drug-mediated enhancement in the activity of T cells of the helper phenotype through elevation in IL-2 production. Antitumor immunity can also facilitate the therapeutic effectiveness of high-dose chemotherapy. Therefore, it is important to determine the conditions under which high-dose chemotherapy can also potentiate host antitumor immunity. From the rodent data available, the picture emerges that the maturity of antitumor immunity at the time of the chemotherapy is an important factor in determining if the high dose of drug leads to immunosuppression or immunopotentiation. When a high dose of drug is administered to tumor bearers with a fully developed antitumor immune response, it is more likely to lead to potentiation of host antitumor immunity than when the high dose of drug is administered to tumor bearers that have not yet achieved the full maturity of their antitumor immune response. In order to achieve the maximal enhancement of antitumor immunity in hitherto immunosuppressed tumor bearers, the suppressor-cell pool should be more sensitive to the toxic effects of the anticancer drugs than are cells involved in immune-tumor eradication.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1993

Effect of anticancer drugs and desferrioxamine in combination with radiation on hepatoma cell lines.

Several anticancer chemotherapeutic agents (5-fluorouracil, adriamycin and cisplatinum) and desferrioxamine, an iron chelator, were tested with regard to cytotoxicity and to the combined effect on radiation induced cell killing using two human hepatoma cell lines (HepG2 and PLC/PRF/5). Survival fractions were measured by quantitative colorimetric assay (MTT assay) and dose-response curves were plotted. MTT assay could be successfully used in the assessment of radiosensitivity in addition to chemosensitivity, because a good linear relationship between optical densities and cell numbers was observed and cells approached exponential growth for the first 7 days of culture when 5 x 10(3) or less cells were inoculated per well in our study. Steepness of the final slope (D0), width of the shoulder (D0) and the extrapolation number (n) of radiation survival curves were 1061.72 rad, 226.43 rad and 1.25 respectively in HepG2 and 1091.38 rad, 268.42 rad and 1.29 respectively in PLC/PRF/5. After combining anticancer chemotherapeutic agents and desferrioxamine with radiation, the widths of the shoulders were decreased whereas sensitizer enhancement ratios were increased as the concentration of drugs increased in both cell lines. These results suggest that neither anticancer chemotherapeutic agents nor desferrioxamine enhance cell killing induced by radiation alone, but suggested the possibility that they inhibit the repair of radiation damage.

Antineoplastic Agents↗

PubMed2005

Selenium protects against toxicity induced by anticancer drugs and augments antitumor activity: a highly selective, new, and novel approach for the treatment of solid tumors.

Limited therapeutic selectivity and tumor resistance are major obstacles to current chemotherapy. The development of new therapeutic modalities for solid tumor remains a challenge. The use of selenium, 5-methylselenocysteine (MSC), or seleno-L-methionine (SLM) as selective modulators of anticancer drugs is novel and has not been previously investigated. Selenium deficiency is associated with an increased risk of cancer and cancer death. Although low-dose selenium supplementation has been investigated in a large randomized prevention trial, its potential in chemotherapy toxicity prevention and enhancement of antitumor activity of anticancer drugs has not been evaluated. An ideal biomodulator of anticancer drugs would allow escalation of drug dose with the hope of enhancing antitumor activity and possibly reversing drug resistance. Results from this laboratory have demonstrated that MSC and SLM are highly effective modulators of irinotecan cure rates in de novo sensitive and resistant human tumor xenografts. Studies in mice have documented that the minimum effective dose of MSC when combined with irinotecan is 0.01 mg daily. The optimal schedule is to administer MSC orally for 7 days before and concurrently with irinotecan. The observed effects were not drug-specific, as similar results were obtained with taxanes, platinum agents, 5-fluorouracil, and anthracyclines; nor were they species-specific, as selective effects were obtained in mice and rats and are currently being confirmed in ongoing clinical trials.

Animals↗