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PubMed2006

Adding pharmacogenomics to the development of new marine-derived anticancer agents.

Nature has always been a highly productive tool in the development of anticancer therapies. Renewed interest in the potential of this tool has recently been sparked by the realization that the marine ecosystem can be used for the discovery and development of new compounds with clinical potential in advanced resistant tumors. These compounds can be incorporated into combination approaches in a chronic therapy scenario. Our marine anticancer program is using the sea to develop new agents with activity in resistant solid tumors and to identify new cellular targets for therapeutic intervention. This review describes the integration of different pharmacogenomic tools in the development of Yondelis, Aplidin and Kahalalide F, three marine-derived compounds currently in Phase II or III development. Our results are reinforcing the targeted selectivity of these agents and opening the gates for customized therapies in cancer patients in the near future.

Journal Article↗

PubMed2005

Anticancer properties of propofol-docosahexaenoate and propofol-eicosapentaenoate on breast cancer cells.

INTRODUCTION: Epidemiological evidence strongly links fish oil, which is rich in docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), with low incidences of several types of cancer. The inhibitory effects of omega-3 polyunsaturated fatty acids on cancer development and progression are supported by studies with cultured cells and animal models. Propofol (2,6-diisopropylphenol) is the most extensively used general anesthetic-sedative agent employed today and is nontoxic to humans at high levels (50 microg/ml). Clinically relevant concentrations of propofol (3 to 8 microg/ml; 20 to 50 microM) have also been reported to have anticancer activities. The present study describes the synthesis, purification, characterization and evaluation of two novel anticancer conjugates, propofol-docosahexaenoate (propofol-DHA) and propofol-eicosapentaenoate (propofol-EPA). METHODS: The conjugates linking an omega-3 fatty acid, either DHA or EPA, with propofol were synthesized and tested for their effects on migration, adhesion and apoptosis on MDA-MB-231 breast cancer cells. RESULTS: At low concentrations (25 microM), DHA, EPA or propofol alone or in combination had minimal effect on cell adhesion to vitronectin, cell migration against serum and the induction of apoptosis (only 5 to 15% of the cells became apoptotic). In contrast, the propofol-DHA or propofol-EPA conjugates significantly inhibited cell adhesion (15 to 30%) and migration (about 50%) and induced apoptosis (about 40%) in breast cancer cells. CONCLUSION: These results suggest that the novel propofol-DHA and propofol-EPA conjugates reported here may be useful for the treatment of breast cancer.

Antineoplastic Agents↗

PubMed2006

Hazardous anticancer drugs in health care: environmental exposure assessment.

Exposure of healthcare workers to anticancer drugs became problematic in the 1970s. Shortly thereafter, studies began documenting exposure of healthcare workers to these drugs. Investigations employing biological markers, such as urine mutagenicity, chromosomal aberrations, sister chromatid exchanges, and micronuclei, demonstrated associations between occupational exposures and elevated marker levels. Other analytical methods emerged to monitor workplaces where drugs were handled. These contemporary studies uncovered widespread contamination of drugs on work surfaces, trace amounts in air samples, and their presence in the urine of workers. Vials containing these drugs are often contaminated with the drug when they are shipped. Most workplace surfaces are contaminated with the drugs being prepared and used in that area. Other anticancer/hazardous drugs would most likely be used in these areas. The interior surfaces of biological safety cabinets and isolators, floors, countertops, carts, storage bins, waste containers, treatment areas, tabletops, chairs, linen, and other items are all potential sources of exposure to anticancer drugs. Patient body fluids contain the drugs and/or metabolites, often more biologically active than the parent compounds. An exposure assessment of areas where anticancer/hazardous drugs are handled must consider every potential source and route of exposure. Data from surface contamination and inhalation studies suggest that dermal exposure is the primary route of exposure. Assessment of exposure is the first step in providing a safe work environment for these workers. However, because of the many drugs to which they are exposed, any assessment can only be an estimation of the overall exposure.

Antineoplastic Agents↗

PubMed2006

Alleviating neurodegeneration by an anticancer agent: an Hsp90 inhibitor (17-AAG).

Heat shock proteins (HSPs) that function mainly as molecular chaperones play an important role in the folding and quality control of proteins. Compared with these chaperones, Hsp90 is unique in that it binds to substrate proteins, called Hsp90 client proteins. Hsp90 is involved in the folding, activation, and assembly of its client proteins in association with its co-chaperones. Because numerous oncoproteins belonging to the Hsp90 client protein family are selectively degraded by Hsp90 inhibitors, 17-allylamino-17-demethoxygeldanamycin (17-AAG), a first-in-class Hsp90 inhibitor, is now under clinical trials as a novel molecular-targeted agent for a wide range of malignancies. In spinal and bulbar muscular atrophy (SBMA), the pathogenic gene product is polyglutamine (polyQ)-expanded androgen receptor (AR), which belongs to the Hsp90 client protein family and is known to be degraded by 17-AAG. We have recently demonstrated that administration of an anticancer agent 17-AAG significantly ameliorated polyQ-mediated motor neuron degeneration by reducing the total amount of mutant AR. The ability of 17-AAG to degrade mutant protein would be directly applicable to SBMA and other neurodegenerative diseases in which the disease-causing proteins also belong to the Hsp90 client protein family. Our proposed therapeutic approach using a novel anticancer agent 17-AAG has emerged as a candidate for molecular-targeted therapies for neurodegenerative diseases.

Animals↗

PubMed2004

Herbal remedies in the United States: potential adverse interactions with anticancer agents.

PURPOSE: Interest in the use of herbal products has grown dramatically in the Western world. Recent estimates suggest an overall prevalence for herbal preparation use of 13% to 63% among cancer patients. With the narrow therapeutic range associated with most anticancer drugs, there is an increasing need for understanding possible adverse drug interactions in medical oncology. METHODS: In this article, a literature overview is provided of known or suspected interactions of the 15 best-selling herbs in the United States with conventional allopathic therapies for cancer. RESULTS: Herbs with the potential to significantly modulate the activity of drug-metabolizing enzymes (notably cytochrome p450 isozymes) and/or the drug transporter P-glycoprotein include garlic (Allium sativum), ginkgo (Ginkgo biloba), echinacea (Echinacea purpurea), ginseng (Panax ginseng), St John' s wort (Hypericum perforatum), and kava (Piper methysticum). All of these products participate in potential pharmacokinetic interactions with anticancer drugs. CONCLUSION: It is suggested that health care professionals and consumers should be aware of the potential for adverse interactions with these herbs, question their patients on their use of them, especially among patients whose disease is not responding to treatments as expected, and urge patients to avoid herbs that could confound their cancer care.

Antineoplastic Agents↗

PubMed2005

Properties of thalidomide and its analogues: implications for anticancer therapy.

Thalidomide and its immunomodulatory (IMiDs) analogs (lenalidomide, Revlimid, CC-5013; CC-4047, ACTIMID) are a novel class of compounds with numerous effects on the body's immune system, some of which are thought to mediate the anticancer and anti-inflammatory results observed in humans. Thalidomide is currently being used experimentally to treat various cancers and inflammatory diseases. It is approved for the treatment of dermal reaction from leprosy and is currently in phase III trials for multiple myeloma. Thalidomide and IMiDs inhibit the cytokines tumor necrosis factor-alpha (TNF-alpha), interleukins (IL) 1beta, 6, 12, and granulocyte macrophage-colony stimulating factor (GM-CSF). They also costimulate primary human T lymphocytes inducing their proliferation, cytokine production, and cytotoxic activity thereby increasing the T cells' anticancer activity. They induce an IL-2-mediated primary T cell proliferation with a concomitant increase in IFN-gamma production and decrease the density of TNF-alpha-induced cell surface adhesion molecules ICAM-1, VCAM-1, and E-selectin on human umbilical vein endothelial cells. Thalidomide stimulates the Th-1 response increasing IFN-gamma levels while CC-4047 increased IL-2 as well. Some of the above immunomodulatory activities along with anti-angiogenic, anti-proliferative, and pro-apoptotic properties are thought to mediate the IMiDs' antitumor responses observed in relapsed and refractory multiple myeloma and some solid tumor cancers. This has led to their use in various oncology clinical trials. The second generation IMiD, lenalidomide, has shown potential in treating the bone marrow disorders myelodysplastic syndrome and multiple myeloma. It is currently in phase II and III trials for these diseases respectively with numerous phase II trials in other hematologic and solid tumors.

Angiogenesis Inhibitors↗

PubMed2001

Synthesis and in-vitro anticancer evaluation of bis-tacrine congeners.

In the search for potential new anticancer drugs, an efficient synthesis of bis-tetrahydroaminoacridine (bis-tacrine) and its congeners was accomplished by bis-amination of 9-chlorotetrahydroacridine and its congeners under heated conditions. The critical chlorides were efficiently prepared from o-aminoaromatic acids and cycloketones in-situ in the presence of phosphorus oxychloride. In-vitro cytotoxic evaluation of the compounds was carried out against a panel of 60 human cancer cell lines. Among them, butyl-linked bis-tacrine (5b) exhibited the strongest cytotoxic profile with GI50 (concentration causing 50% growth inhibition) values of approximately 0.04-0.08 microM against breast, colon, melanoma and non-small lung cancer cells. Congeners bearing a longer alkyl chain were on average 30- to 100-fold less cytotoxic against these cancer cells. Shorter connecting alkyl chains of bis-tacrine or its congeners dramatically decreased the cytotoxic effects. Compound 5b has been selected for further biological evaluation of its anticancer profile.

Cholinesterase Inhibitors↗

PubMed2003

Interferon-beta is more potent than interferon-alpha in inhibition of human hepatocellular carcinoma cell growth when used alone and in combination with anticancer drugs.

BACKGROUND: The prognosis of advanced hepatocellular carcinoma (HCC) is extremely poor, but promising effects of chemotherapies combined with interferon (IFN) have been reported. METHODS: To develop more effective combination therapies for HCC, we compared the antiproliferative effects of IFN-alpha and IFN-beta in combination with various cytotoxic drugs on hepatoma cell lines using MTT assay and isobologram analysis. RESULTS: IFN-beta was more potent than IFN-alpha in inhibiting the cell growth of all cell lines (P <.05, two-way ANOVA). PLC/PRF/5 was more sensitive to either IFN, than HLE and HuH7. Cell growth of all cell lines was inhibited in a dose-dependent manner by 5-fluorouracil (5-FU), cisplatin (CDDP), and doxorubicin (DOX), but the sensitivities of these cells were considerably different. As for IFN-alpha, synergistic effects were observed when combined with 5-FU and DOX on PLC/PRF/5 cells only, whereas IFN-beta showed synergistic effects with 5-FU and CDDP on HuH7 and PLC/PRF/5 cell lines. CONCLUSION: The spectra of the antiproliferative activity and synergistic effect of IFN-beta when combined with anticancer drugs are more potent than those of IFN-alpha. Combinations of IFN-beta and anticancer drugs may provide a better treatment of HCC when combinations with IFN-alpha are ineffective.

Analysis of Variance↗

PubMed2002

Cytotoxic effects of 27 anticancer drugs in HeLa and MDR1-overexpressing derivative cell lines.

The cytotoxic effects of 27 anticancer drugs including amrubicin, vinorelbine, paclitaxel, docetaxel, gemcitabine, and irinotecan were evaluated in human cervical carcinoma HeLa cells, and drug-resistant HeLa-derived Hvrl-1, HvrlO-6, and Hvr100-6 cells, which were newly established by stepwise exposure to vinblastine. FACS and RT-PCR analysis indicated that MDR1 (P-glycoprotein) was induced without any alterations in expression of its related transporters. Hvrl00-6 cells showed 2- to 200-fold higher resistance to anthracyclines than HeLa cells, and unexpectedly showed slight resistance to idarubicin and amrubicin. The relative resistance to vinca-alkaloids was 300- to 600,000-fold, and HvrlOO-6 cells showed the highest relative resistance to vinorelbine. HvrlOO-6 cells also showed 4000- and 60000-fold resistance to the taxanes paclitaxel and docetaxel, respectively. Hvr100-6 cells were also resistant to 6-mercaptopurine, actinomycin D, etoposide, and mitomycin C, with relative resistance of 8-, 45000-, 12-, and 9-fold, respectively. In contrast, HvrlOO-6 cells showed no or slight resistance to platinum derivatives, pyrimidine analogues, and alkylating agents or to irinotecan and its active form, or tamoxifen. The cytotoxicity of anthracyclines, vinca-alkaloids, taxanes, actinomycin D, and etoposide was extensively reversed by cyclosporin A. Cyclosporin A had no effect on the cytotoxicity of 6-mercaptopurine or mitomycin C, suggesting that resistance to these drugs was not mediated via MDR1. The alterations in cytotoxicity by overexpression of MDR1 and effects of cyclosporin A could be also qualitatively explained by [3H]vinblastine uptake experiments. The 27 anticancer drugs analyzed here could be classified into substrates and nonsubstrates for MDR1. This will be useful for designing effective regimens for chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Differential cytotoxicity of anticancer agents in pre- and post-immortal lymphoblastoid cell lines.

We studied the cytotoxic effect of various anticancer agents on lymphoblastoid cell lines transformed by Epstein-Barr virus. Post-immortal N0005 (post-N0005) is an immortalized cell line derived from pre-immortal N0005 (pre-N0005) accompanied by increased telomerase activity, short-telomere, abnormal karyotypes, mutation of p53 gene, down regulation of p16/Rb and the ability to grow in soft agar medium. Compared with pre-N0005 cells, post-N0005 cells were significantly (p<0.001 by the Student t test) more resistant to the killing activity of seven DNA-modifying agents: camptothecin, etoposide, bleomycin, fluorouracil, thioguanine, melphalan and actinomycin D. However, both pre-N0005 and post-N0005 cells showed similar levels of cytotoxicity against four DNA-non-modifying agents: colchicine, paclitaxel, vincristine and methotrexate. DNA-modifying and DNA-non-modifying agents are distinguished by their different sensitivities with pre-N0005 and post-N0005. Based on these results, we propose that pre-N0005 and post-N0005 cell lines be used as a new method to assess and screen anticancer agents.

Antineoplastic Agents↗

PubMed2006

Poloxamer 188 and propylene glycol-based rectal suppository enhances anticancer effect of 5-fluorouracil in mice.

The tumoricidal and apoptosis-inducing activities of 5-fluorouracil (5-FU) have been demonstrated in experimental and clinical investigations. Clinically, the 5-FU suppository form has been widely adopted for its advantages of less systemic toxicity, higher local tissue concentrations, and reduced first-pass effect. In this study, we investigated the feasibility of rectal administration of 5-FU suppository based on poloxamer 188 (P188) and propylene glycol (PG) and its anticancer effect on the murine experimental cancer models. The rectal suppository was made with 70% P188 and 30% PG, which was a solid phase at room temperature and instantly melted at physiological temperature. The treatment with the 5-FU suppository was more effective than the oral route in decreasing the volume of rectal cancer in mice. In addition, the survival rate of the mice with rectal cancer was higher in the group treated with the 5-FU suppository than in the group treated with 5-FU orally. Furthermore, in mice skin cancers induced by inoculation of murine CT-26 colon carcinoma cells, the anticancer effect of 5-FU was significantly enhanced by the rectal administration of the suppository than by oral treatment. Taken together, the results suggest that a poloxamer gel system with 5-FU/P188/PG is an effective rectal dosage form for the treatment of both rectal and non-rectal cancers.

Administration, Rectal↗

PubMed1986

Evaluation of anticancer drugs by lymphocyte electrophoresis.

The spleen cells in tumor-bearing and normal mice treated with Krestin (PSK), mitomycin C (MMC) or adriamycin (ADM) were analyzed by cell electrophoresis and flow microcytometry. In normal mice, the splenocyte electrophoretic mobility histogram was observed as a bimodal pattern, and low and high mobility cells (LMC and HMC) corresponded with B and T cells, respectively. In sarcoma-180-bearing mice, an intermediate mobility peak (IMC) appeared between the low and high peaks. Although every anticancer drug depressed the IMC when the tumor was cured, MMC reduced the absolute number of splenic Ig+ and Thy-1+ cells, and ADM injured Ig+ cells in normal as well as in tumor-bearing mice. PSK, however, depressed splenomegaly by tumor-burden in spite of a slight increase in splenocytes of normal mice. In a previous paper, it was reported that the thymocyte mobility histogram was restored to a normal pattern by treatment with PSK in tumor-bearers, while it was made more abnormal by treatment with MMC because of injury to cortical thymocytes. From these results, it may be considered that an anticancer drug which restored the splenocyte mobility histogram to a normal pattern without damages to thymocytes is preferable for cancer therapy.

Animals↗

PubMed2004

[Serotonin and anticancer drug-induced emesis].

Cytotoxic drug-induced nausea and vomiting are the side effects most feared by cancer patients. Emesis is an instinctive defense reaction caused by the somato-autonomic nerve reflex, which is integrated in the medulla oblongata. Emesis caused by anticancer drugs is associated with an increase in the concentration of serotonin (5-HT) (5-HT) in the intestinal mucosa and brainstem. 5-HT released from the enterochromaffin (EC) cells, which synthesize and secrete 5-HT, stimulates the 5-HT receptors on the adjacent vagal afferent nerves. The depolarization of the vagal afferent nerves stimulates the vomiting center in the brainstem and eventually induces a vomiting reflex. 5-HT released from EC cells appears to mediate the cisplatin-induced emesis sensitive to 5-HT(3) receptor antagonists. The precise role of 5-HT in the occurrence of vomiting has not been fully elucidated. The present review describes the role of 5-HT in anticancer drug-induced emesis from the viewpoint of 5-HT release and afferent vagal nerve activity. Various models and methods for predicting emesis are also evaluated.

Animals↗

PubMed2002

Cysteine-modifying agents: a possible approach for effective anticancer and antiviral drugs.

Modification of cysteine residues in proteins, due to a) the participation of the thiol moiety of this amino acid in oxido-reduction reactions, b) its ability to strongly coordinate transition metal ions, or c) its nucleophilic nature and facile reaction with electrophiles, may be critically important for the design of novel types of pharmacological agents. Application of such procedures recently led to the design of novel antivirals, mainly based on the reaction of zinc finger proteins with disulfides and related derivatives. This approach was particularly successful for developing novel antiviral agents for human immunodeficiency virus and human papilloma virus. Several new anticancer therapeutic approaches, mainly targeting tubulin, have also been reported. Thus, this unique amino acid offers very interesting possibilities for developing particularly useful pharmacological agents, which generally possess a completely different mechanism of action compared with classic agents in clinical use, thus avoiding major problems such as multidrug resistance (for antiviral and anticancer agents) or high toxicity.

Antineoplastic Agents↗

PubMed2004

cDNA microarray gene expression analysis and toxicological phenotype for anticancer drug.

Toxicogenomics, the subdiscipline that merges genomics with toxicology, hold the promise to contributing toward the goal of elucidating mechanism by studying genomic profiling related with various drugs. The application of gene expression profiling technology to examine multiple genes and signaling pathways promises a significant advance in understanding the toxic mechanisms of various drugs and prediction of new drug candidate. Toxicogenomics is emerging field combining genomics and bioinformatics to identify and characterize mechanisms of toxicity of drug and various compounds. The principal hypothesis underlying on this field is that chemical-specific pattern of altered gene expression is related with each chemicals properties, especially toxicological property, and it will be revealed using high-density microarray analysis of sample from exposed organisms. So, in this study we compare the gene expression pattern of two anticancer drugs paclitaxel and orally absorbable paclitaxel, using the cDNA microarray. And from the result of this study, it is possible to provide the new possibility for genome-wide insight into mechanism of their anticancer activity and toxicological phenotype.

Administration, Oral↗

PubMed2004

Moraxella osloensis blood and catheter infections during anticancer chemotherapy: clinical and microbiologic studies of 10 cases.

Moraxella osloensis, a gram-negative bacterium that is saprophytic on skin and mucosa, rarely causes infections. Moreover, infections in patients with cancer have not been reported. We describe 10 cases of M. osloensis blood or catheter infections that occurred during anticancer chemotherapy with or without preexisting neutropenia. The organism was identified definitively by sequencing analysis of the 16S ribosomal RNA gene. Fever (up to 39.7 degrees C) with substantial neutrophilia characterized these infections. The infections were monomicrobic for 3 patients and polymicrobic for 7 patients. Nine patients acquired the infection through central venous catheter colonization. The likely sources of the organism were sinusitis (3 cases), bronchitis (1 case), presumed subclinical mucositis from anticancer therapy (4 cases), and cutaneous graft-vs-host disease (2 cases). The infections resolved, without catheter removal, after antibiotic therapy with cell wall-active agents, to which all strains were shown to be susceptible. The M. osloensis strains exhibited significant morphologic variations on gram stain, and sheep blood agar was the preferred culture medium for 9 strains.

Adult↗

PubMed2003

Anticancer antibodies.

The recent clinical and commercial success of anticancer antibodies such as rituximab and trastuzumab has created great interest in antibody-based therapeutics for hematopoietic malignant neoplasms and solid tumors. Given the likelihood of lower toxic effects of antibodies that target tumor cells and have limited impact on nonmalignant bystander organs vs small molecules, the potential increased efficacy by conjugation to radioisotopes and other cellular toxins, and the ability to characterize the target with clinical laboratory diagnostics to improve the drug's clinical performance, current and future antibody therapeutics are likely to find substantial roles alone and in combination therapeutic strategies for treating patients with cancer. It also is likely that conjugation strategies will add new radiolabeled and toxin-linked products to the market to complement the recent approvals of ibritumomab tiuxetan and gemtuzumab ozogamicin. This review considers the structure of anticancer therapeutic antibodies and the techniques used to reduce their antigenicity. Efficacy and toxic effects, conjugation with isotopes and toxins, and validation of the antibody targets also are discussed. Antibodies approved by the Food and Drug Administration are described in detail, as are antibodies in late and early stages of clinical development.

Animals↗

PubMed1998

Pharmacokinetics of anticancer drugs in cerebrospinal fluid.

OBJECTIVE: To examine the pharmacokinetics of anticancer drugs in the cerebrospinal fluid (CSF) during chemotherapy by the lumbar-ventricular (LV) and ventricular-lumbar (VL) routes. CASE SUMMARY: A 69-year-old Japanese woman with disseminated glioblastoma received two LV and four VL courses of CSF perfusion chemotherapy with methotrexate, nimustine, and cytarabine hydrochloride. Samples of CSF from the ventricles and lumbar spinal canal were obtained via Ommaya reservoirs during one LV and one VL course. Drug concentrations in the CSF were measured by fluorescence polarization immunoassay or HPLC. RESULTS: During LV CSF perfusion, the highest CSF drug concentrations in both the ventricles and the lumbar spinal canal were observed at the end of perfusion. During treatment, the concentrations of all three drugs in the lumbar spinal canal were higher than those in the ventricles. The CSF AUC of methotrexate in the ventricles was 16.1% of that in the lumbar spinal canal. During VL CSF perfusion, the highest drug concentrations were also observed at the end of perfusion. The drug concentrations in the lumbar spinal canal were initially lower than those in the ventricles. However, the concentrations of methotrexate and cytarabine in the lumbar spinal canal exceeded those in the ventricles 3 hours after perfusion. The AUC of methotrexate in the lumbar spinal canal was 174.9% of that in the ventricles. CONCLUSIONS: The pharmacokinetics of anticancer drugs in ventricular CSF differ from those in lumbar CSF during LV and VL perfusion chemotherapy.

Aged↗