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Molecular & General Genetics : MGG Jul 1990Rhizoxin, an antibiotic, exhibits potent anti-mitotic activity against most eucaryotic cells including those of higher vertebrates, plants and fungi by binding to...
Rhizoxin, an antibiotic, exhibits potent anti-mitotic activity against most eucaryotic cells including those of higher vertebrates, plants and fungi by binding to beta-tubulin. The benA gene of three independently isolated rhizoxin-resistant (Rhir) mutants of Aspergillus nidulans was cloned, sequenced and compared with that of the wild-type, rhizoxin-sensitive (Rhis) strain. In all three Rhir mutants, the AAC codon for Asn-100 of the benA beta-tubulin gene was altered to ATC, coding for Ile. Sequence displacement experiments confirmed that the substitution of Ile for Asn-100 confers resistance to rhizoxin in this organism. The amino acid sequences of beta-tubulin surrounding the 100th amino acid residue from the N-terminus including Asn-100 are highly conserved with a few exceptions. The fission yeast Schizosaccharomyces pombe and the budding yeast Saccharomyces cerevisiae are naturally occurring Rhir organisms whose beta-tubulin genes encode Ile and Val respectively at the 100th amino acid residue. The Ile-100 of S. pombe and the Val-100 of S. cerevisiae were altered to Asn using site-directed mutagenesis and gene displacement techniques. The resultant haploid strains of these two yeasts uniquely expressing beta-tubulin (Asn-100) instead of beta-tubulin (Ile-100 or Val-100) were found to be Rhis. Haploid yeast expressing beta-tubulin (Asn-100) is normal except for its sensitivity to rhizoxin. These results suggest that rhizoxin resistance has a common basis in both naturally occurring species and experimentally selected mutants in the substitution of Ile or Val for Asn-100 in beta-tubulin.
Topics: Amino Acid Sequence; Antifungal Agents; Aspergillus nidulans; Base Sequence; Blotting, Southern; Cloning, Molecular; Codon; DNA, Fungal; Drug Resistance, Microbial; Genes, Fungal; Lactones; Macrolides; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation; Restriction Mapping; Saccharomyces cerevisiae; Schizosaccharomyces; Sequence Homology, Nucleic Acid; Transformation, Genetic; Tubulin
PubMed: 2274023
DOI: 10.1007/BF00633814 -
Biopharmaceutics & Drug Disposition Mar 1994The tumour uptake as well as the anti-tumour activity of RS-1541 (palmitoyl rhizoxin), a potent antineoplastic agent, were investigated in mice bearing M5076 sarcoma....
The tumour uptake as well as the anti-tumour activity of RS-1541 (palmitoyl rhizoxin), a potent antineoplastic agent, were investigated in mice bearing M5076 sarcoma. After intravenous administration, 14C-RS-1541 preferentially bound to the lipoproteins, to which 14C-rhizoxin did not bind. 14C-RS-1541 showed persisting high concentrations of radioactivity in the plasma (T 1/2 alpha, 4.9 h). The uptake of radioactivity by the tumour was second to those by the liver and spleen, and several times greater than those by the other tissues. Selective and sustained uptake by the tumour was also demonstrated by whole-body autoradiography. A considerable amount of rhizoxin was detected only in the tumour after administration of 14C-RS-1541, and the area under the tissue-concentration-time curve (AUCt) and the mean residence time (MRT) of rhizoxin in the tumour were much higher than those after administration of 14C-rhizoxin itself. The rhizoxin formation in the tumour was significantly reduced by chloroquine, a lysosomal enzyme inhibitor. RS-1541 showed a higher therapeutic activity than rhizoxin. At a 4 mg kg-1 dose, the maximum growth inhibition was 92% for RS-1541 and 41% for rhizoxin. These results indicate that RS-1541, but not rhizoxin, is taken up by the tumour via endocytosis, most likely via the low-density-lipoprotein receptor, after binding to lipoproteins. Thus, RS-1541 was considered to exhibit sustained high concentration in tumours and potent anti-tumour activity.
Topics: Animals; Antineoplastic Agents; Autoradiography; Carbon Radioisotopes; Chloroquine; Female; In Vitro Techniques; Lactones; Lipoproteins, LDL; Macrolides; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neoplasm Transplantation; Protein Binding; Sarcoma, Experimental; Skin Neoplasms; Tissue Distribution
PubMed: 8011970
DOI: 10.1002/bdd.2510150202 -
Gan To Kagaku Ryoho. Cancer &... Jul 1993Rhizoxin is a new macrocyclic lactone isolated from the fungus Rhizopus chinensis. In an attempt to predict the effectiveness of rhizoxin in the treatment of lung... (Comparative Study)
Comparative Study
Rhizoxin is a new macrocyclic lactone isolated from the fungus Rhizopus chinensis. In an attempt to predict the effectiveness of rhizoxin in the treatment of lung cancer, we compared the antitumor activity of rhizoxin with those of cisplatin and etoposide using four small cell lung cancer (SCLC) cell lines, SBC-2, -3, -4, and -7, and two non-small cell lung cancer (NSCLC) cell lines, ABC-1 and EBC-1. The concentrations producing 50% inhibition of the growth of these cell lines (IC50) for each drug were obtained by MTT assay. The IC50 of rhizoxin for these cell lines ranged 0.408 nM to 1.56 nM, which were significant lower than those of cisplatin (660 nM to 16,300 nM) and etoposide (275 nM to 31,300 nM). The ratio of IC50 for the most sensitive cell line, SBC-3, to that for the most resistant cell line was less than 4-fold in rhizoxin, in contrast to more than 20-fold in cisplatin and 100-fold in etoposide. Cross-resistance of rhizoxin to cisplatin and etoposide was investigated using a cisplatin-resistant SCLC subline, SBC-3/CDDP, and an etoposide-resistant SCLC subline, SBC-3/ETP. Of interest, the parent cell line, and the resistant sublines were equally sensitive to rhizoxin, indicating rhizoxin being non-cross-resistant to cisplatin and etoposide. In conclusion, rhizoxin may be beneficial in the salvage chemotherapy of drug-resistant SCLC and non-SCLC.
Topics: Antibiotics, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cisplatin; Drug Resistance; Drug Screening Assays, Antitumor; Etoposide; Humans; Lactones; Lung Neoplasms; Macrolides; Tumor Cells, Cultured
PubMed: 8392827
DOI: No ID Found -
Cancer Research Jan 1986Rhizoxin, isolated from a plant pathogenic fungus which causes rice seedling blight, inhibits the mitosis of the tumor cells in a manner similar to that of Vinca...
Rhizoxin, isolated from a plant pathogenic fungus which causes rice seedling blight, inhibits the mitosis of the tumor cells in a manner similar to that of Vinca alkaloids as revealed by morphological study and flow cytometry analysis. This new 16-membered macrocyclic lactone showed similar chemotherapeutic effects to those of vincristine against L1210 and P388 leukemia-bearing mice. The drug is also effective against B16 melanoma inoculated i.p. or s.c. Rhizoxin, in contrast to the ansamacrolide, maytansine, was effective against human and murine tumor cells resistant to vincristine and Adriamycin in vitro and in vivo. A maximum 60% increase in life span was obtained in mice inoculated with P388 leukemia resistant to vincristine. Rhizoxin showed greater cytotoxicity in cultured tumor cells than did vincristine. Rhizoxin seems to bear consideration for further development as a new chemotherapeutic agent.
Topics: Animals; Antibiotics, Antineoplastic; Cell Cycle; Cells, Cultured; Drug Resistance; Female; Lactones; Leukemia L1210; Leukemia P388; Leukemia, Experimental; Macrolides; Maytansine; Melanoma; Mice; Microscopy, Electron, Scanning
PubMed: 3753552
DOI: No ID Found -
Journal of Natural Products Mar 2009This review provides an overview of the discovery, structures, and biological activities of anticancer natural products that act by inhibiting or promoting the assembly... (Review)
Review
This review provides an overview of the discovery, structures, and biological activities of anticancer natural products that act by inhibiting or promoting the assembly of tubulin to microtubules. The emphasis is on providing recent information on those compounds in clinical use or in advanced clinical trials. The vinca alkaloids, the combretastatins, NPI-2358, the halichondrin B analogue eribulin, dolastatin 10, noscapine, hemiasterlin, and rhizoxin are discussed as tubulin polymerization inhibitors, while the taxanes and the epothilones are the major classes of tubulin polymerization promoters presented, with brief treatments of discodermolide, eleutherobin, and laulimalide. The challenges and future directions of tubulin-interactive natural products-based drug discovery programs are also discussed briefly.
Topics: Antineoplastic Agents; Biological Products; Diketopiperazines; Imidazoles; Microtubules; Molecular Structure; Piperazines; Tubulin; Vinca Alkaloids
PubMed: 19125622
DOI: 10.1021/np800568j -
Journal of the National Cancer Institute Apr 1992Rhizoxin is a new macrocyclic lactone isolated from the fungus Rhizopus chinensis which displays broad-spectrum antitumor activity against murine and human tumor... (Clinical Trial)
Clinical Trial Comparative Study
BACKGROUND
Rhizoxin is a new macrocyclic lactone isolated from the fungus Rhizopus chinensis which displays broad-spectrum antitumor activity against murine and human tumor xenografts and has activity against a number of vincristine-resistant tumors in vitro and in vivo.
PURPOSE
This study describes the preclinical and clinical pharmacology of rhizoxin to apply a pharmacokinetically guided dose-escalation (PGDE) strategy during the phase I trial.
METHODS
Rhizoxin was administered by a single intravenous bolus injection to female BALB/c mice over the dose range 7.5-18 mg/m2 from which we derived the dose that was lethal to 10% and 50% of the mice (i.e., LD10 and LD50, respectively). The LD10 was 11.7 +/- 0.7 mg/m2 (mean +/- SD), and the LD50 was 14.7 +/- 0.6 mg/m2. Pharmacokinetic studies were integrated with the toxicity study in female BALB/c mice at one-tenth the LD10, one-half the LD10, and the LD10 (i.e., 1.2, 6, and 12 mg/m2, respectively). From these data, a target area under the plasma drug concentration versus time curve (AUC) (i.e., 40% of the LD10 AUC) was calculated for clinical studies. Phase I studies were initiated at 0.8 mg/m2 (one-tenth the equivalent LD10 in male CD1 mice), with the intent of escalating the dose by an extended factor-of-two method until the target AUC and/or maximum tolerated dose (MTD) was reached.
RESULTS
The major drug toxic effects in mice were body weight loss, sluggishness, ataxia, transient changes in hematological parameters, and hematuria. Diarrhea was universal at doses greater than 9 mg/m2, and hind limb paralysis was observed in one of 10 mice, but only at supralethal doses (18 mg/m2). Rhizoxin pharmacokinetics were best described by a two-compartment open model (half-life [t 1/2] alpha = 4.4 minutes +/- 0.9 minute [mean +/- SD], and t 1/2 beta = 84 minutes +/- 20 minutes at 12 mg/m2) and found to be nonlinear with respect to dose. At doses of 1.2, 6, and 12 mg/m2, the respective AUC values were 1.3, 22.4, and 70.6 microM x minute. From these data, a target AUC value of 28 microM x minute (40% of the LD10 AUC) was derived. Rhizoxin was not detectable in patient plasma (less than 5 ng/mL at 0.8 and 1.6 mg/m2), and doses had to be escalated by conventional methods. Myelosuppression was dose limiting in patients: Seven of eight treated at 2.6 mg/m2 experienced World Health Organization grade 3-4 neutropenia, and five of eight developed mucositis. The AUC values at the human MTD (2.6 mg/m2) were in the range of 0.41-1.01 microM x minute, considerably lower than the target AUC of 28 microM x minute.
CONCLUSION AND IMPLICATIONS
Although PGDE schemes have been successfully employed for other antitumor agents, this methodology could not be applied during the phase I trial of rhizoxin. PGDE studies in the future may incorporate comparative murine versus human metabolism studies in vitro with phenotyped liver microsomes. It may also be useful to assess the comparative myelotoxicity of a new drug by performing in vitro cytotoxicity studies on mouse and human bone marrow stem cells.
Topics: Adolescent; Adult; Aged; Animals; Antibiotics, Antineoplastic; Blood Proteins; Drug Evaluation; Drug Screening Assays, Antitumor; Female; Humans; Lactones; Macrolides; Mice; Mice, Inbred BALB C; Middle Aged
PubMed: 1545439
DOI: 10.1093/jnci/84.7.494 -
Tanpakushitsu Kakusan Koso. Protein,... Aug 1993
Review
Topics: Animals; Binding Sites; Colchicine; Lactones; Ligands; Macrolides; Maytansine; Tubulin; Tubulin Modulators; Vinblastine
PubMed: 8210422
DOI: No ID Found -
Angewandte Chemie (International Ed. in... Feb 2010
Topics: Chemistry, Pharmaceutical; Macrolides; Models, Biological; Molecular Structure
PubMed: 20033973
DOI: 10.1002/anie.200905467 -
Dose-response : a Publication of... 2019The role of viral infection in developing cancer was determined in the start of 20th century. Until now, 8 different virus-associated cancers have been discovered and... (Review)
Review
The role of viral infection in developing cancer was determined in the start of 20th century. Until now, 8 different virus-associated cancers have been discovered and most of them progressed in immunosuppressed individuals. The aim of the present study is to look into the benefits of natural products in treating virally infected cancers. The study focuses on bioactive compounds derived from natural sources. Numerous pharmaceutical agents have been identified from plants (vincristine, vinblastine, stilbenes, combretastatin, and silymarin), marine organisms (bryostatins, cephalostatin, ecteinascidins, didemnin, and dolastatin), insects (cantharidin, mastoparan, parectadial, and cecropins), and microorganisms (vancomycin, rhizoxin, ansamitocins, mitomycin, and rapamycin). Beside these, various compounds have been observed from fruits and vegetables which can be utilized in anticancer therapy. These include curcumin in turmeric, resveratrol in red grapes, S-allyl cysteine in allium, allicin in garlic, catechins in green tea, and β-carotene in carrots. The present study addresses various types of virally infected cancers, their mechanism of action, and the role of different cell surface molecules elicited during viral binding and entry into the target cell along with the anticancer drugs derived from natural products by targeting screening of bioactive compounds from natural sources.
PubMed: 30670935
DOI: 10.1177/1559325818813227 -
Cancer Research May 1992Rhizoxin is a tubulin-binding cytotoxic compound, isolated from the fungus Rhizopus chinensis, with significant antineoplastic activity in several murine and human tumor... (Clinical Trial)
Clinical Trial
Rhizoxin is a tubulin-binding cytotoxic compound, isolated from the fungus Rhizopus chinensis, with significant antineoplastic activity in several murine and human tumor models. In this Phase I study, the drug was administered by i.v. bolus injection at 3-wk intervals. Twenty-four patients with refractory solid tumors were treated; 60 courses of rhizoxin were given, at doses ranging from 0.8 to 2.6 mg/m2. Grade 3 mucositis, Grade 4 leukopenia, and Grade 3 diarrhea were dose limiting but reversible at 2.6 mg/m2, the maximum tolerated dose for both previously untreated and heavily pretreated patients. Alopecia and moderate discomfort at the injection site occurred at all doses. Other sequelae, including peripheral neuropathy, phlebitis, and nausea and vomiting, were sporadic and mild. Two heavily pretreated patients with recurrent breast cancer had minor responses to rhizoxin, one at 1.6 mg/m2 and the other at 2.6 mg/m2. Plasma concentrations of rhizoxin were measured by high-performance liquid chromatography. The drug was not detectable (less than 5 ng/ml) at doses of 0.8 mg/m2 and 1.6 mg/m2 and was not measurable 10 min after injection at 2.0 mg/m2. At 2.6 mg/m2, there was considerable intersubject variation in the plasma concentration-time profiles; the area under the curve ranged from 0.29 to 0.96 microgram/ml.min. Rhizoxin has shown some clinical activity in this Phase I study, and a dose of 2.0 mg/m2 is recommended for Phase II studies using this schedule.
Topics: Adult; Aged; Animals; Antibiotics, Antineoplastic; Body Weight; Diarrhea; Drug Administration Schedule; Drug Evaluation; Female; Hindlimb; Humans; Injections, Intraperitoneal; Lactones; Leukopenia; Macrolides; Male; Middle Aged; Neoplasms; Paralysis
PubMed: 1581905
DOI: No ID Found