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British Journal of Cancer Feb 1996To test the anti-tumour activity of rhizoxin in recurrent and/or metastatic squamous cell head and neck cancer, we performed a phase II study. Eligibility required... (Clinical Trial)
Clinical Trial
To test the anti-tumour activity of rhizoxin in recurrent and/or metastatic squamous cell head and neck cancer, we performed a phase II study. Eligibility required histologically proven squamous cell head and neck cancer. Patients could only have received one prior chemotherapy. Patients were entered if WHO PS was < or = 2 and organ functions were normal. Treatment consisted of rhizoxin 1.5-2.0 mg m-2 i.v. bolus injection once every 3 weeks. Thirty-two patients entered the study. All were eligible, 31 were evaluable for toxicity and 25 for response. Toxicity mainly consisted of pain at the tumour site and leucocytopenia. Mild asthenia and stomatitis were also observed. Two objective partial responses, lasting 7.5 and 3.5 months, were seen. Rhizoxin at this dose and schedule has minor activity in recurrent and/or metastatic squamous cell head and neck cancer.
Topics: Adult; Aged; Antibiotics, Antineoplastic; Carcinoma, Squamous Cell; Female; Head and Neck Neoplasms; Humans; Lactones; Macrolides; Male; Middle Aged
PubMed: 8562350
DOI: 10.1038/bjc.1996.69 -
Annals of Oncology : Official Journal... Nov 1992
Clinical Trial
Topics: Animals; Antibiotics, Antineoplastic; Drug Evaluation; Drug Resistance; Humans; Lactones; Macrolides; Neoplasms, Experimental
PubMed: 1450059
DOI: 10.1093/oxfordjournals.annonc.a058321 -
Pharmacology & Therapeutics Nov 1991The interaction of antimitotic drugs with guanine nucleotides in the tubulin-microtubule system is reviewed. Antimitotic agent-tubulin interactions can be covalent,... (Review)
Review
The interaction of antimitotic drugs with guanine nucleotides in the tubulin-microtubule system is reviewed. Antimitotic agent-tubulin interactions can be covalent, entropic, allosteric or coupled to other equilibria (such as divalent cation binding, alternate polymer formation, or the stabilization of native tubulin structure). Antimitotics bind to tubulin at a few common sites and alter the ability of tubulin to form microtubules. Colchicine and podophyllotoxin compete for a common overlapping binding site but only colchicine induces GTPase activity and large conformational changes in the tubulin heterodimer. The vinca alkaloids, vinblastine and vincristine, the macrocyclic ansa macrolides, maytansine and ansamitocin P-3, and the fungal antimitotic, rhizoxin, share and compete for a different binding site near the exchangeable nucleotide binding site. The macrocyclic heptapeptide, phomopsin A, and the depsipeptide, dolastatin 10, bind to a site adjacent to the vinca alkaloid and nucleotide sites. Colchicine, vinca alkaloids, dolastatin 10 and phomopsin A induce alternate polymer formation (sheets for colchicine, spirals for vinblastine and vincristine and rings for dolastatin 10 and phomopsin A). Maytansine, ansamitocin P-3 and rhizoxin inhibit vinblastine-induced spiral formation. Taxol stoichiometrically induces microtubule formation and, in the presence of GTP, assembly-associated GTP hydrolysis. Analogs of guanine nucleotides also alter polymer morphology. Thus, sites on tubulin for drugs and nucleotides communicate allosterically with the interfaces that form longitudinal and lateral contacts within a microtubule. Microtubule associated proteins (MAPs), divalent cations, and buffer components can alter the surface interactions of tubulin and thus modulate the interactions between antimitotic drugs and guanine nucleotides.
Topics: Animals; Antineoplastic Agents; Drug Interactions; Humans; Microtubules; Nucleotides; Protein Binding; Tubulin
PubMed: 1818332
DOI: 10.1016/0163-7258(91)90004-6 -
Gan To Kagaku Ryoho. Cancer &... Sep 1997Microtubules are one of the major filament of the cytoskelton and play a role in various biological functions such as mitosis, cell motility and intracellular transport.... (Review)
Review
Microtubules are one of the major filament of the cytoskelton and play a role in various biological functions such as mitosis, cell motility and intracellular transport. Therefore, microtubules are considered one of the most important molecular targets for cancer chemotherapy. Tubulin is one of the major microtubular components, and its polymerization and depolymerization regulate microtubular dynamics. Other microtubular components such as microtubule-associated protein (MAPs), actin, and intermediate and microfilaments have also been demonstrated to be involved in microtubular dynamics. Recent studies provide evidence that the functions of MAPs and filaments in microtubule assembly are regulated by phosphorylation, which is catalyzed by mitogenactivated protein kinase (MAP kinase) and cdc2 kinase. Antimitotic agents that disrupt microtubules can be classified in two categories according to the mechanism of action, vinca alkaloids and taxanes. Vinca alkoloids, estramustine, rhizoxin, and E7010 inhibit microtubule polymerization. In contrast, taxanes such as paclitaxel and docetaxel promote polymerization of microtubules and enhance microtubule stability. We have demonstrated that paclitaxel inhibits the catalytic activity of MAP kinase and cdc2 kinase in lung cancer cell lines. This biological effect may be responsible for the increased affinity between MAP2 and tubulins, resulting in promotion of microtubule assembly. Factors that contribute to the resistance to antimitotic agents include intracellular accumulation of the drugs, genetic or functional alternations in tubulin, and alternations in MAP kinase cascade. Antimitotic agents showed a broad spectrum of preclinical antitumor activity. Clinical trials of taxanes revealed that they were effective for several cancers which were advanced or resistant against other anticancer drugs, especially for breast cancers, ovarian cancers and non-small cell lung cancers.
Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Calcium-Calmodulin-Dependent Protein Kinases; Carcinoma, Small Cell; Drosophila Proteins; Estramustine; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Lung Neoplasms; Mice; Microtubules; Ovarian Neoplasms; Paclitaxel; Vinca Alkaloids
PubMed: 9309150
DOI: No ID Found -
Environmental Health : a Global Access... Jun 2024Risk assessment (RA) of microbial secondary metabolites (SM) is part of the EU approval process for microbial active substances (AS) used in plant protection products... (Review)
Review
Risk assessment (RA) of microbial secondary metabolites (SM) is part of the EU approval process for microbial active substances (AS) used in plant protection products (PPP). As the number of potentially produced microbial SM may be high for a certain microbial strain and existing information on the metabolites often are low, data gaps are frequently identified during the RA. Often, RA cannot conclusively clarify the toxicological relevance of the individual substances. This work presents data and RA conclusions on four metabolites, Beauvericin, 2,3-deepoxy-2,3-didehydro-rhizoxin (DDR), Leucinostatin A and Swainsonin in detail as examples for the challenging process of RA. To overcome the problem of incomplete assessment reports, RA of microbial AS for PPP is in need of new approaches. In view of the Next Generation Risk Assessment (NGRA), the combination of literature data, omic-methods, in vitro and in silico methods combined in adverse outcome pathways (AOPs) can be used for an efficient and targeted identification and assessment of metabolites of concern (MoC).
Topics: Risk Assessment; European Union; Secondary Metabolism; Depsipeptides; Humans
PubMed: 38835048
DOI: 10.1186/s12940-024-01092-0 -
British Journal of Cancer Feb 1996Rhizoxin is a new anti-tumour agent isolated from the pathogenic fungus Rhizopus chinensis. It has shown broad activity against murine tumour models and is also active... (Clinical Trial)
Clinical Trial
Rhizoxin is a new anti-tumour agent isolated from the pathogenic fungus Rhizopus chinensis. It has shown broad activity against murine tumour models and is also active against vinca alkaloid-resistant cells. The purpose of our studies was to determine the clinical activity of this compound in patients with advanced breast cancer and melanoma. Based on the results of a phase I study, 2.0 mg m-2 was administered as intravenous infusion over 5 min every 21 days. Nineteen patients were entered into the breast cancer phase II trial and received a total of 50 courses (median 2, range 1-6). Of these, dose reductions were performed in three courses because of leucopenia or stomatitis (1.5 mg m-2, one course; 1.45 mg m-2, two courses). Twenty-six patients were entered into the melanoma trial and received a total of 70 courses (median 2, range 1-12). No dose reductions were required. All patients were eligible for toxicity. Haematological toxicity included neutropenia CTC grade 3 (29/120 courses, 24.2%) and grade 4 (11/20 courses, 9.2%). Only drug-related CTC grade 1 thrombocytopenia was observed. Non-haematological toxicity included alopecia in all patients after two courses of treatment as well as CTC grade 3/4 stomatitis and asthenia. In the breast cancer study, one patient achieved a more than 50% tumour reduction after six cycles but was progressing after 6 weeks. Another patient showed a partial remission after the first course but was taken off the study because of CTC grade 3 skin toxicity. One patient was not evaluable for response (early death). No objective remissions were observed in 15 evaluable patients. In melanoma, no objective remissions were observed. We conclude that rhizoxin can be safely administered at 2.0 mg m-2 every 3 weeks. However, it has little activity in patients with advanced breast cancer and melanoma.
Topics: Adult; Aged; Antibiotics, Antineoplastic; Breast Neoplasms; Female; Hematopoiesis; Humans; Lactones; Macrolides; Male; Melanoma; Middle Aged
PubMed: 8562349
DOI: 10.1038/bjc.1996.68 -
Current Opinion in Oncology Dec 1992New drug discovery continues to follow the time-honored paths of screening and novel target identification combined with analogue development and serendipity. The agents... (Clinical Trial)
Clinical Trial Review
New drug discovery continues to follow the time-honored paths of screening and novel target identification combined with analogue development and serendipity. The agents selected here reflect these various approaches. They include drugs already showing significant antitumor activity, eg, anthrapyrazoles, temozolomide, camptothecin analogues, and taxotere, and updated information is provided on their development. Other drugs just entering or currently in phase I trials include rhizoxin, which seems capable of overcoming multidrug resistance; the novel bioreductive agent EO9 [corrected]; and bryostatin, a highly potent protein kinase C agonist. Sequence specificity could well prove to be an important factor in the development of DNA-interactive agents, and information is provided on the progress with distamycin mustard and the new cyclopropylpyrroloindole analogues carzelesin and adozelesin.
Topics: Antineoplastic Agents; Bryostatins; Camptothecin; Docetaxel; Humans; Lactones; Macrolides; Neoplasms; Paclitaxel; Taxoids
PubMed: 1360819
DOI: 10.1097/00001622-199212000-00011 -
Biochemical Pharmacology Apr 1993The rhizoxin (RZX)-binding site on porcine brain tubulin was investigated by photoaffinity labeling with the 5-azido-1-naphthalene sulfonyl (azidodansyl) derivative of...
The rhizoxin (RZX)-binding site on porcine brain tubulin was investigated by photoaffinity labeling with the 5-azido-1-naphthalene sulfonyl (azidodansyl) derivative of RZX, nor-rhizoxin-22-al-5'-azidonaphthalene-1'-sulfonylhydrazo ne (azidodansylrhizoxin: Adan-RZX). Upon ultraviolet irradiation, Adan-RZX generates a highly reactive nitrene, which irreversibly binds to an amino acid residue(s) near the RZX-binding site. The label was found to be on beta-tubulin. Enzymatic digestion of the labeled tubulin generated only one major fluorescent peak on C18 reverse phase HPLC analysis. The labeled site(s) was mapped by using various combinations of highly specific peptidases in succession. That is, the labeled fragment generated by the first peptidase was purified by HPLC and exposed to a second peptidase; if the retention time in HPLC changed after the second digestion, the fragment generated in the first digestion must have contained the recognition site(s) of the second enzyme. From the results of these successive digestions and the known polypeptide sequences, we could identify the labeled fragment as Met-363-Lys-379 of beta-tubulin. This peptidase combination technique should be widely applicable.
Topics: Affinity Labels; Amino Acid Sequence; Animals; Binding Sites; Endopeptidases; Lactones; Lysine; Macrolides; Metalloendopeptidases; Methionine; Molecular Sequence Data; Naphthalenesulfonates; Peptides; Serine Endopeptidases; Swine; Tubulin
PubMed: 8471064
DOI: 10.1016/0006-2952(93)90036-v -
Proceedings of the National Academy of... Sep 2014
Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Female; Humans; Macrolides; Maytansine; Microtubules; Polyketides; Pyrones; Tubulin; Tubulin Modulators
PubMed: 25187564
DOI: 10.1073/pnas.1414572111 -
Medicinal Research Reviews Jul 1998Tubulin is the biochemical target for several clinically used anticancer drugs, including paclitaxel and the vinca alkaloids vincristine and vinblastine. This review... (Review)
Review
Tubulin is the biochemical target for several clinically used anticancer drugs, including paclitaxel and the vinca alkaloids vincristine and vinblastine. This review describes both the natural and synthetic agents which are known to interact with tubulin. Syntheses of the more complex agents are referenced and the potential clinical use of the compounds is discussed. This review describes the biochemistry of tubulin, microtubules, and the mitotic spindle. The agents are discussed in relation to the type of binding site on the protein with which they interact. These are the colchicine, vinca alkaloid, rhizoxin/maytansine, and tubulin sulfhydryl binding sites. Also included are the agents which either bind at other sites or unknown sites on tubulin. The literature is reviewed up to October 1997.
Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Binding Sites; Colchicine; Drug Design; Humans; Lactones; Macrolides; Maytansine; Microtubules; Paclitaxel; Protein Binding; Spindle Apparatus; Sulfhydryl Reagents; Tubulin; Tubulin Modulators; Vinblastine; Vincristine
PubMed: 9664292
DOI: 10.1002/(sici)1098-1128(199807)18:4<259::aid-med3>3.0.co;2-u