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Molecular and Cellular Biochemistry Nov 2003Studies on vinca domain binding drugs were done in great details by a number of workers as it is recognized as a potential target for anticancer drug development. Their... (Review)
Review
Studies on vinca domain binding drugs were done in great details by a number of workers as it is recognized as a potential target for anticancer drug development. Their structures, properties, mode of action, success and failures as potential anticancer drug have been discussed in short details in this review. Among these drugs rhizoxin and maytansine are competitive inhibitors, and bind at the vinblastine binding site of tubulin where as others are non-competitive inhibitors. Besides binding, these drugs also differ in the extent of GTP hydrolysis, GTP exchange and in the stabilization of colchicine binding site. The toxicity level of these drugs towards the host cells and the extent of efflux of drugs by the P-glycoprotein mediated pump are also discussed.
Topics: Animals; Antineoplastic Agents; Binding Sites; Humans; Microtubules; Protein Structure, Tertiary; Tubulin; Tubulin Modulators; Vinca Alkaloids
PubMed: 14619954
DOI: 10.1023/a:1026045100219 -
Biochemical and Biophysical Research... Jul 1991A fluorescent probe (D-RZX) and a photoreactive fluorescent probe (AD-RZX) for studying the rhizoxin binding site on tubulin were prepared by the derivatization of...
A fluorescent probe (D-RZX) and a photoreactive fluorescent probe (AD-RZX) for studying the rhizoxin binding site on tubulin were prepared by the derivatization of rhizoxin (RZX). D-RZX consists of a rhizoxin moiety and a dansyl moiety. AD-RZX has a 5-azidonaphthalene-1-sulfonyl moiety instead of the dansyl moiety of D-RZX. Both D-RZX and AD-RZX bound tubulin in a mutually competitive manner with rhizoxin, indicating their binding to the rhizoxin site on tubulin. AD-RZX bound the rhizoxin site covalently after UV-irradiation, thus showing its usefulness as a photo-affinity probe for labeling of the rhizoxin site.
Topics: Affinity Labels; Animals; Binding Sites; Brain; Fluorescent Dyes; Kinetics; Lactones; Macrolides; Microtubule Proteins; Swine; Tubulin
PubMed: 1859416
DOI: 10.1016/0006-291x(91)90144-v -
Cancer Chemotherapy and Pharmacology 2000In previous phase I reports of short bolus infusion of rhizoxin, problems in assay sensitivity prevented the description of pharmacokinetic-pharmacodynamic... (Clinical Trial)
Clinical Trial
In previous phase I reports of short bolus infusion of rhizoxin, problems in assay sensitivity prevented the description of pharmacokinetic-pharmacodynamic relationships, and a pharmacologically guided approach to dose escalation was deemed not feasible. In this report, we describe a mathematical model, which explains the schedule-dependent interpatient pharmacodynamic variability of rhizoxin administered on a continuous infusion schedule. Using patient demographic and toxicity data from 45 patients treated in a phase I dose and duration escalation study of rhizoxin, we sought to model the nadir neutrophil count. We hypothesized that a surrogate derived variable based on dose and duration would reflect a pharmacokinetic parameter that would be a significant covariate. Multiple linear regression analysis was carried out to determine the other significant covariates. Dose/m2 x Log(DUR/ALB) was significantly correlated with the LogANCnadir (Log10 neutrophil nadir; r = 0.56, P < 0.001). Other significant covariates included baseline performance status (PS), baseline serum bilirubin (BIL), and Log10 baseline neutrophil count (LogANCbaseline). Model bias and precision were assessed using the mean prediction error (MPE) and the root mean square error (RMSE) of the ANCnadir, respectively. We constructed 1-4 covariate models. The variability of ANCnadir was modeled with good precision and accuracy with a 4-covariate model (MPE and RMSE 0.113 +/- 0.182 x 10(3) cells/microl and 1.22 x 10(3) cells/microl, respectively). This model should be validated and improved on with further clinical data. We believe that such pharmacodynamic modeling should be explored further to determine its performance and clinical relevance compared with modeling using pharmacokinetic parameters.
Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Drug Administration Schedule; Female; Humans; Lactones; Macrolides; Male; Middle Aged; Models, Biological
PubMed: 10854137
DOI: 10.1007/s002800051024 -
Annals of Oncology : Official Journal... Nov 1992Rhizoxin is a 16-membered antifungal macrocyclic lactone isolated from the plant pathogenic fungus Rhizopus chinensis. The compound binds to tubulin, preventing...
Rhizoxin is a 16-membered antifungal macrocyclic lactone isolated from the plant pathogenic fungus Rhizopus chinensis. The compound binds to tubulin, preventing microtubule formation, and inhibiting mitosis. It possesses antitumour activity in vivo against various preclinical murine models, both leukaemias and solid tumours model, as well as in vincristine- and doxorubicin-resistant leukaemia lines. In the present study, cytotoxic activity was observed in human tumour cell lines in vitro at very low concentrations (+/- 10(-10) M) particularly against melanoma, colon, renal, non-small cell and small cell lung cancer. In vivo antitumour activity was demonstrated in murine P388 and L1210 murine leukaemias, solid tumour models B16 melanoma and M5076 sarcoma, and in 5 out of 9 human solid tumour xenografts: LOX melanoma, MX-1 breast cancer, non-small cell lung cancer A549, and small cell lung cancers LXFS 605 and LXFS 650. The absence of cross-resistance to vinca alkaloids was confirmed in vivo against the vincristine-resistant P388 leukaemia subline and the vincristine-resistant human small cell lung cancer LXFS 650. In addition, the antitumour activity of rhizoxin was improved by prolonged or repeated drug administration indicating a schedule dependency. In animal toxicology studies, transient changes in erythrocyte and leukocyte numbers, local phlebitis, diarrhea, and spermatogenic arrest were observed. The LD10 value of rhizoxin after a single intravenous injection was 2.8 mg/kg (8.4 mg/m2). One-tenth of the mouse equivalent LD10 (0.84 mg/m2), the starting dose for clinical phase I studies, was considered to be safe in rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Animals; Antibiotics, Antineoplastic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Screening Assays, Antitumor; Humans; Injections, Intraperitoneal; Injections, Intravenous; Lactones; Lethal Dose 50; Macrolides; Male; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental; Rats; Rats, Wistar; Tumor Cells, Cultured
PubMed: 1450065
DOI: 10.1093/oxfordjournals.annonc.a058334 -
Organic Letters Apr 2004[structure: see text] A convergent, stereoselective total synthesis of the macrolide antitumor agent rhizoxin D is described. (+)-DIPCl-promoted asymmetric aldol...
[structure: see text] A convergent, stereoselective total synthesis of the macrolide antitumor agent rhizoxin D is described. (+)-DIPCl-promoted asymmetric aldol reaction, Evans-Tishchenko 1,3-diol synthesis, modified Julia coupling, and Horner-Wadsworth-Emmons reactions are featured.
Topics: Antineoplastic Agents; Lactones; Macrolides; Molecular Conformation; Stereoisomerism
PubMed: 15101763
DOI: 10.1021/ol049701h -
Organic & Biomolecular Chemistry Jul 2007Targeted gene inactivation and metabolic profiling revealed that the cryptic PKS-NRPS gene cluster in the genome of the plant commensal Pseudomonas fluorescens Pf-5...
Targeted gene inactivation and metabolic profiling revealed that the cryptic PKS-NRPS gene cluster in the genome of the plant commensal Pseudomonas fluorescens Pf-5 codes for the biosynthesis of antiproliferative and antifungal rhizoxin derivatives.
Topics: Antimitotic Agents; Genes, Bacterial; Genome, Bacterial; Macrolides; Models, Biological; Pseudomonas fluorescens
PubMed: 17609750
DOI: 10.1039/b707762a -
Gan To Kagaku Ryoho. Cancer &... Apr 1994Microtubules, which are composed of polymerized tubulin dimers, play an important role in various cell functions. For example, they maintain cell shape, form mitotic... (Review)
Review
Microtubules, which are composed of polymerized tubulin dimers, play an important role in various cell functions. For example, they maintain cell shape, form mitotic spindles in M phase of cell cycle, and carry an axonal transport in nerve cells. Microtubules have also been an important target of cancer chemotherapy. Vinca alkaloids depolymerize microtubules, the mechanisms of which action have extensively been investigated recently. Clinical trials of vinorelbine (navelbine), a new semisynthetic vinca alkaloid, are ongoing in Japan. One of advantages of the drug is reduced risk of neurotoxicity. Estramustine may act on microtubule-associated proteins (MAPs) as well as tubulin. It shows additive or synergistic cytotoxicity preclinically when used in combination with vinblastine. This combination was active against hormone-refractory prostate cancer. Another novel drug rhizoxin, which has a similar mechanism of action to that of vinca alkaloids, is also a promising cytotoxic agent and is examined clinically in Europe. Taxanes, which include paclitaxel (Taxol) and taxotere, are interesting drugs because they promote polymerization of tubulin and stabilize microtubules. They show promising antitumor activity against breast, ovarian and lung cancers. Phase I and II trials are ongoing in Japan. Paclitaxel may also potentiate cytotoxicity of radiation. There are several mechanisms of resistance to microtubule-acting drugs. One is multidrug resistance mediated by P-glycoprotein. Other mechanisms include mutation of tubulin.
Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Female; Humans; Lactones; Lung Neoplasms; Macrolides; Microtubule-Associated Proteins; Microtubules; Ovarian Neoplasms; Paclitaxel; Tubulin; Vinca Alkaloids
PubMed: 7908790
DOI: No ID Found -
The Journal of Antibiotics Jan 1987The mode of action of rhizoxin (1a), a new antitumor macrolide, was investigated. Rhizoxin inhibited fusion of the male and the female pronuclei in fertilized sea urchin... (Comparative Study)
Comparative Study
The mode of action of rhizoxin (1a), a new antitumor macrolide, was investigated. Rhizoxin inhibited fusion of the male and the female pronuclei in fertilized sea urchin eggs and inhibited cilia formation in the deciliated sea urchin embryos. In vitro, polymerization of tubulin isolated from porcine brains was completely inhibited at a 1 X 10(-5) M concentration of rhizoxin, and tubulin which had been polymerized by incubation at 37 degrees C for 30 minutes was depolymerized by addition of 1 X 10(-5) M of the drug. Activity of rhizoxin against tubulin polymerization was compared with those of other anti-tubulin drugs such as colchicine, vinblastine and ansamitocin P-3. The homologues of rhizoxin, 1b-3b, also inhibited polymerization of the purified microtuble protein at almost the same extent as rhizoxin.
Topics: Animals; Antibiotics, Antineoplastic; Brain; Female; Lactones; Macrolides; Male; Microtubules; Mitosis; Rhizopus; Sea Urchins; Structure-Activity Relationship; Swine; Tubulin; Zygote
PubMed: 3606749
DOI: 10.7164/antibiotics.40.66 -
Japanese Journal of Cancer Research :... Dec 1997Previous studies by our and other groups have shown that microbial products containing more than one epoxide group, including eponemycin, radicicol, depudecin and...
Previous studies by our and other groups have shown that microbial products containing more than one epoxide group, including eponemycin, radicicol, depudecin and AGM-1470, exhibits anti-angio-genic activity in an in vivo assay system involving chorioallantoic membranes (CAMs) of growing chick embryos. Based on these findings, rhizoxin, a microbial metabolite that contains two epoxide groups and exhibits anti-tubulin activity, was tested for anti-angiogenic activity in a CAM assay system. Rhizoxin caused dose-dependent inhibition of embryonic angiogenesis, the ID50 value being 2 ng (3.2 pmol) per egg. In addition, this compound (2 mg/kg i.p.) significantly suppressed neovascularization induced by M5076 mouse tumor cells in a mouse dorsal air sac assay system, compared to the vehicle alone (P < 0.05). These results indicate that rhizoxin is a novel inhibitor of angiogenesis, and that is has potential as a new therapeutic agent for cancer.
Topics: Animals; Antibiotics, Antineoplastic; Chick Embryo; Dose-Response Relationship, Drug; Epoxy Compounds; Lactones; Macrolides; Mice; Neovascularization, Pathologic; Neovascularization, Physiologic; Spinal Neoplasms; Spinal Nerve Roots
PubMed: 9473728
DOI: 10.1111/j.1349-7006.1997.tb00339.x -
The Journal of Organic Chemistry May 2003The convergent, highly enantioselective synthesis of rhizoxin D, a natural product possessing potent antitumor and antifungal bioactivity, is described. The C(1)-C(9)...
The convergent, highly enantioselective synthesis of rhizoxin D, a natural product possessing potent antitumor and antifungal bioactivity, is described. The C(1)-C(9) fragment of the molecule was synthesized utilizing a threefold pseudosymmetric intermediate ultimately derived from gamma-butyrolactone. The central core of rhizoxin D was prepared via a chiral resolution/asymmetric aldol protocol. Several methods for the generation of the polyene fragment were explored, and the side-chain was ultimately prepared from serine in six steps. The unification of the left and right wings of the molecule was achieved using a one-step olefination protocol, and the macrocyclization was carried out using a Horner-Emmons olefination at the C(2)-C(3) olefin.
Topics: Alkenes; Antineoplastic Agents; Catalysis; Cyclization; Indicators and Reagents; Lactones; Macrolides; Molecular Structure; Stereoisomerism
PubMed: 12762720
DOI: 10.1021/jo034011x