glaucarubin and bruceantin

Topics: Animals; Antineoplastic Agents, Phytogenic; Cells, Cultured; Drug Evaluation; Drug Evaluation, Preclinical; Ellipticines; Glaucarubin; Harringtonines; Humans; Podophyllotoxin; Pyrrolizidine Alkaloids; Quassins

In an effort to discover new chemotherapeutic/chemopreventive agents from natural sources, brusatol (1) was found to induce HL-60 cellular differentiation, accompanied by strong antiproliferative and cytotoxic effects. A series of natural and semisynthetic quassinoids (1-48) was designed to effect both antiproliferative and differentiation-inducing properties. Compounds were assessed in vitro using the HL-60 promyelocytic cell model. Changes in activity due to structural modification of the core structure glaucarubolone (24) were consistent with activities reported in other cell systems. However, the following were novel SAR findings: (1) semisynthetic analogues with a hydroxylated ring at the beta-position of the ester side chain at C-15 were able to induce cellular differentiation at concentrations lower than those inducing cell growth arrest, and (2) quassinoids inhibiting DNA synthesis with greater efficacy than reducing cellular viability possessed alkyl substitutions at the alpha-position of the C-15 ester side chain. Analogues from this latter group and brusatol (1) and bruceantin (2) inhibited dimethylbenz(a)anthracene-induced preneoplastic lesion formation in a mouse mammary organ culture. The novel finding of 1 and glaucarubolone analogues as potent inducers of differentiation leads to potential novel applications in the field of cancer.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Cell Differentiation; Cell Division; Cell Membrane; DNA; Drug Screening Assays, Antitumor; Female; Glaucarubin; Glycosylation; HL-60 Cells; Humans; Inhibitory Concentration 50; Mammary Neoplasms, Animal; Mice; Mice, Inbred BALB C; Models, Biological; Molecular Structure; Nitroblue Tetrazolium; Organ Culture Techniques; Plants, Medicinal; Quassins; Rats; Simaroubaceae; Structure-Activity Relationship; Time Factors; Tumor Cells, Cultured

The C-15 senecioyl side chain of brusatol was interchanged with fluorinated acyl groups, and the C-3 hydroxy group of bruceolide was esterified with fluorinated acyl chlorides. These fluorinated quassinoids 11, 12, 13, and 17 showed significant cytotoxic activity against eight human cancer cell lines including small and non-small cell lung, colon, CNS, ovarian and renal cancers, leukemia, and melanoma with 17 being about 100 times more potent than 11, 12, and 13. The activity of 17 was similar to that of bruceantin (1) in this in vitro cell line panel.

Topics: Acylation; Antineoplastic Agents, Phytogenic; Fluorine; Glaucarubin; Humans; Models, Chemical; Quassins; Tumor Cells, Cultured

Girodazole (RP 49532A) or 3-amino-1-[4-(2 amino-1H-imidazolyl]-propanol, 2HCl is an experimental antitumor compound which inhibits protein synthesis in cell cultures and in cell free systems. The compound has been evaluated for its capacity to inhibit specific assays of initiation, elongation and termination of protein synthesis. Girodazole inhibited the release of nascent peptides from polyribosomes in rabbit reticulocyte lysates indicating that the major effect of the compound is on the protein synthesis termination step.

Topics: Animals; Antineoplastic Agents; Glaucarubin; Globins; Imidazoles; Peptide Chain Elongation, Translational; Peptide Chain Termination, Translational; Polyribosomes; Propanolamines; Protein Biosynthesis; Quassins; Rabbits; Reticulocytes; Trichothecenes

A microdilution technique for the assessment of in vitro activity against Entamoeba histolytica was devised and validated with metronidazole. The test was used to detect the antiamoebic activities of plant extracts prepared from the traditional remedies Brucea javanica fruits and Simarouba amara stems. The activity was associated with quassinoid-containing fractions. The 50% inhibitory concentrations for some quassinoids against amoebae were determined by using the microdilution method. These concentrations ranged from 0.019 micrograms.ml-1 for bruceantin, the most active quassinoid, to greater than 5 micrograms.ml-1 for glaucarubol, the least active compound tested. These results are discussed with reference to the known activities of these compounds against Plasmodium falciparum. Overall, the activities of the quassinoids against both protozoa are similar. The microdilution technique will be useful in the search for novel antiamoebic drugs.

Topics: Amebicides; Animals; Entamoeba histolytica; Fruit; Glaucarubin; Indicator Dilution Techniques; Metronidazole; Microchemistry; Phenanthrenes; Plant Extracts; Plants, Medicinal; Plasmodium falciparum; Quassins

Patients with objectively measurable soft tissue sarcoma, bone sarcoma, or mesothelioma who had failed at least one prior chemotherapy regimen received either bleomycin (20 U/M2 i.v. day 1 each week), chlorozotocin (150 mg/M2 i.v. q6 weeks), MGBG (500 mg/M2 i.v. each week, escalated in 50 mg/M2 weekly increments to a maximum dose of 700 mg/M2), or bruceantin (5.5 mg/M2 days 1, 8, 15, and 22, with cycles repeated every 6 weeks). One hundred eighty patients were evaluable: 53 on bleomycin, 51 on chlorozotocin, 38 on MGBG, and 38 on bruceantin. Two partial responses resulted from bleomycin, and one each from chlorozotocin and MGBG. Both responders on bleomycin had mesothelioma. Seventy-four percent of the patients were of ECOG performance status 0 or 1, and over half on each arm had moderate or worse toxicity. At these doses and schedules, none of the four drugs tested was active against previously treated sarcomas. Bleomycin, however, should be considered for further evaluation in mesothelioma patients.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Phytogenic; Bleomycin; Bone Neoplasms; Drug Evaluation; Female; Glaucarubin; Humans; Male; Mesothelioma; Middle Aged; Mitoguazone; Phenanthrenes; Quassins; Sarcoma; Soft Tissue Neoplasms; Streptozocin

Topics: Animals; Antineoplastic Agents, Phytogenic; Blood Proteins; Glaucarubin; In Vitro Techniques; Phenanthrenes; Protein Biosynthesis; Quassins; Rabbits; Reticulocytes

Topics: Animals; Antimalarials; Glaucarubin; Phenanthrenes; Plasmodium falciparum; Quassins

The Eastern Cooperative Oncology Group (ECOG) conducted a Phase II trial of Bruceantin in malignant melanoma. Twenty-two patients, thirteen without prior cytotoxic chemotherapy, were entered. All patients were evaluable for response and toxicity. Dose limiting toxicity was found to be hypotension during Bruceantin infusion. Other prominent side effects were nausea, vomiting, anorexia, fever, chills, and weakness. Only minor hematologic toxicity was encountered. Two partial responses, both in previously treated patients were observed (response rate -9%). Bruceantin has only limited activity against malignant melanoma and is unlikely to contribute to systemic therapy of this disease, either as a single agent or in combinations of cytotoxic drugs.

Topics: Aged; Antineoplastic Agents, Phytogenic; Drug Evaluation; Female; Glaucarubin; Humans; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Phenanthrenes; Quassins

Bruceantin, purified from an Ethiopian plant used to treat dysentery, killed Entamoeba histolytica in vitro (IC50 [the concentration of drug which decreased the number of colonies to half that of controls] = 0.018 microgram/ml). Six related quassinoids of 17 tested were also amoebicidal. No relationship between quassinoid structure and amoebicidal activity was apparent.

Topics: Amebicides; Animals; Drug Evaluation, Preclinical; Drug Resistance; Entamoeba histolytica; Glaucarubin; Phenanthrenes; Plant Extracts; Plants, Medicinal; Quassins; Structure-Activity Relationship

Topics: Amebicides; Animals; Antineoplastic Agents, Phytogenic; Entamoeba histolytica; Glaucarubin; Phenanthrenes; Quassins

A phase II evaluation of bruceantin was carried out in 15 patients with refractory metastatic breast cancer. All patients had received extensive prior therapy including adriamycin, cytoxan, 5-FU, methotrexate, and a vinca alkaloid. Except for two patients with stable disease, no complete or partial response was observed. Drug toxicity, mainly nonhematologic, was severe, with nausea, vomiting, mild hypotension, and fever being the most frequently encountered.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Drug Evaluation; Female; Glaucarubin; Humans; Hypotension; Leukocyte Count; Middle Aged; Nausea; Neoplasm Metastasis; Phenanthrenes; Quassins; Vomiting

During the phase I clinical trial of a new antitumor agent, bruceantin, the pharmacology was studied in 18 cancer patients. The drug was infused intravenously (IV) for 3 h at doses ranging from 1 to 3.6 mg/m2 per day for 5 days. The plasma drug disappearance curves were biphasic, with a fast initial half-life of less than 15 min. The second half-life (t1/2 beta) varied from 0.7 to 38 h among different patients and was not dose-related. The difference between the t1/2 beta on day 1 and that on day 5 was not significant. In patients with normal liver function, the mean plasma concentration at the end of infusion was 22 ng/ml, and the value of the area under the concentration X time curve (AUC) was 111 (ng/ml)h. In contrast, in patients with abnormal liver function the corresponding values were 115 ng/ml and 830 (ng/ml)h, respectively. In addition, these patients had a slower elimination half-life of 10.9 h and a decreased total clearance of 157 ml/min/m2, as compared with 2.6 h and 671 ml/min/m2, respectively, for the normal group. All these differences were statistically significant. Patients with abnormal liver function developed more severe toxicity, including fever, severe nausea, vomiting, and hypotension. Two patients with severe hepatic dysfunction received a reduced dose and developed no toxicity. These results demonstrated the importance of the effects of liver dysfunction on drug disposition and showed that the dosage should be reduced in patients with hepatic dysfunction.

Topics: Antineoplastic Agents, Phytogenic; Drug Evaluation; Glaucarubin; Half-Life; Humans; Hypotension; Infusions, Parenteral; Liver; Neoplasms; Phenanthrenes; Quassins; Radioimmunoassay

Based on the fact that some known antineoplastic agents possess an ester moiety within their structure, the esters of helenalin, a sesquiterpene lactone, and of brusatol and bruceantin, quassinoids, were synthesized and tested for antileukemic activity in the P-388 screen. These agents gave different T/C% values dependent on the P-388 lymphocytic leukemia strain and the host strain of mice used. Later studies demonstrated that the agents caused different degrees of inhibition of nucleic acid and protein synthesis in the various P-388 strains. The higher the degree of inhibition of precursor incorporation into the nucleic acid or protein, the higher was the T/C% value obtained in a given P-388 strain. The study demonstrates the lack of consistency of P-388 lymphocytic leukemia cell lines used in various laboratories and indicates that the inbred strain of mice is a critical factor in the tolerance of drug toxicity and, thus, T/C% obtained.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cells, Cultured; DNA, Neoplasm; Glaucarubin; Leukemia P388; Leukemia, Experimental; Male; Mice; Mice, Inbred Strains; Neoplasm Proteins; Phenanthrenes; Quassins; Sesquiterpenes; Sesquiterpenes, Guaiane; Thymidine

Topics: Animals; Glaucarubin; Globins; Kinetics; Peptide Chain Initiation, Translational; Poly U; Puromycin; Pyrans; Quassins; Reticulocytes; RNA, Messenger

Topics: Animals; Antineoplastic Agents, Phytogenic; Bile; Dogs; Female; Glaucarubin; Mice; Mice, Inbred DBA; Phenanthrenes; Quassins; Radioimmunoassay; Tissue Distribution

Topics: Animals; Antineoplastic Agents, Phytogenic; Glaucarubin; Kidney; Leukemia L1210; Liver; Lung; Male; Mice; Mice, Inbred Strains; Microsomes; Pyrans; Quassins; Time Factors; Tissue Distribution