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At least 109 records · Page 6Linked to original sources
PubMed1987

Evaluation of new anticancer agents against human pancreatic carcinomas in nude mice.

Heterotransplantation of human cancers in nude mice has provided an in vivo model for studying the biologic characteristics of human tumors, particularly their response to chemotherapy. In an effort to identify cytotoxic agents effective against pancreatic carcinoma, this model was used to evaluate the efficacy of three new anticancer agents--menogarol, 4'-epirubicin, and taxol--against two human transplanted pancreatic tumors. Relative area (tumor length X width) differed significantly between menogarol-treated and control groups (p = 0.034). A marked response was also observed in the tumors to 4'-epirubicin (p = 0.01). Taxol was ineffective in controlling tumor growth; by the fourth week, the size of treated tumors was similar to that of the control group (p = 0.55). No toxicity was observed in either the menogarol- or taxol-treated animals. Animals bearing the P2 tumor, and treated with 4' epirubicin displayed severe toxicity by day 18 with death by day 21 in most animals. For the second tumor, Capan-1, relative area differed significantly between the menogarol-treated and the control group (p = 0.003). In animals given 4'-epirubicin, a smaller difference was observed when comparing the relative areas (p = 0.09). Animals treated with taxol again showed no difference in the tumors when compared with controls (p = 1.0). The use of the nude mouse system has evolved so that tumor-oriented trials are now feasible with the hope of clinical applicability. This study illustrates that at least two agents--menogarol and 4'-epirubicin--may have some antitumor activity against pancreatic carcinoma in this system.

Adult↗
PubMed1988

Phase II trial of menogarol in the treatment of advanced adenocarcinoma of the pancreas.

Fifteen patients with advanced adenocarcinoma of the pancreas were treated with menogarol 150-225 mg/m2 i.v. every 3 weeks. All patients had bidimensionally measurable disease. This regimen and dosage schedule are well tolerated, with minimal toxicity that included myelosupression; median white blood cell (WBC) count nadir of 2,700 cells/mm3 (range 1,400-7,100 cells/mm3) and median platelet nadir of 162,000 cells/mm3 (range 53,000-390,000 cells/mm3). Anorexia occurred in one patient, nausea or vomiting in six, phlebitis in one, and alopecia in six patients. No patients responded. At this dosage and schedule, there is no role for menogarol in the treatment of advanced pancreatic adenocarcinoma.

Adenocarcinoma↗
PubMed1998

New agents in the treatment of small cell lung cancer.

The treatment of small cell lung cancer (SCLC) has evolved significantly over the past 3 decades. Single-agent and combination chemotherapies given with radiotherapy have greatly improved response rates and median survival. Combination regimens such as cisplatin/etoposide, carboplatin/etoposide, ifosfamide/carboplatin/etoposide, cyclophosphamide/doxorubicin/vincristine, and etoposide/ifosfamide/cisplatin have all achieved good response rates. Improving long-term survival, however, has remained problematic. Treatment with biological response modifiers (interferons alpha and gamma) has not shown promise in this setting. New agents showing good preliminary single-agent activity in untreated SCLC include paclitaxel, vinorelbine, gemcitabine, topotecan, and teniposide. Results obtained with single-agent docetaxel and CPT-11 are thus far inconclusive. Studies evaluating response and survival rates of these new agents in combination with agents of known activity are underway.

Antibiotics, Antineoplastic↗
PubMed1992

[New anthracycline analogues in the treatment of lung cancer].

Doxorubicin is one of the most potent drugs for the treatment of small cell lung cancer (SCLC), but less potent for non-small eell lung cancer (NSCLC). The prevalent use of doxorubicin is limited by the development of cardiomyopathy. Therefore, TUT-7 SM-5887, and ME2303 have been under the clinical studies to find new anthracyclines with less cardiotoxicity and higher therapeutic indices not only for SCLC but also for NSCLC. The dose-limiting factor of these drugs determined in phase I studies was leukocytopenia. Phase II studies which are currently under way have indicated that SM-5887 is possibly most potent for the treatment of NSCLC, and that these drugs have less cardiotoxicity compared to the mother compound, doxorubicin.

Anthracyclines↗
PubMed1990

[Antitumor spectrum of TUT-7 on rat ascitic hepatoma].

The antitumor activity of TUT-7, a new anthracycline compound, was compared to that of adriamycin in the screening system with rat ascites hepatomas. A marked antitumor effect was observed in most tumor lines, and the activity was assumed to be better than adriamycin.

Animals↗
PubMed1990

[Antitumor activities of orally administered 7-con-0-methylnogarol (TUT-7)].

We estimated antitumor activity of TUT-7 following p.o. administration using animal tumor models and human tumor xenografts. In mouse L 1210 leukemia system, antitumor activity of TUT-7 administered orally was as good as that by i.v. administration. Treatment involving schedules of every 4-days or daily administration was much more effective than single treatment. Therapiotic indices of this compound administered both p.o. or i.v. routes, were better than that of adriamycin administered i.v.. TUT-7 showed antitumor activities against various mouse tumors (L 1210 leukemia, P 388 leukemia, colon 38 adenocarcinoma, B 16 melanoma), LX-1 human tumor xenografts, and Yoshida sarcoma in rat. Base on above results, we concluded that oral administration is one of the useful route of TUT-7 administration.

Administration, Oral↗
PubMedDate not supplied

The disposition of the new anthracycline antibiotic, menogarol, in mice.

We have investigated the metabolism and disposition, in mice, of 7-con-O-methylnogarol ( menogarol ; 7-OMEN), a new anthracycline antibiotic entering clinical trials. 7-OMEN, dissolved in 0.01 M glucuronic acid, was administered iv to mice (10 mg/kg). At specified times after injection, groups of mice were killed and 7-OMEN and metabolites were assayed in plasma and organs by HPLC. Plasma concentrations of 7-OMEN declined in triexponential fashion. The terminal t1/2 was 10.6 hr; the AUC was 10.13 microM X hr; the apparent Vc was 0.4 liter/m2, and the systemic clearance was 91.2 ml/min/m2. One metabolite, with the same HPLC characteristics as N- demethylmenogarol , was seen in plasma during the first 30 min after injection. 7-OMEN was distributed extensively to all tissues except brain. Initially, pulmonary concentrations of 7-OMEN were 15 times higher than those in any other organ and 30 times higher than those in plasma. Concentrations of 7-OMEN were the most persistent in spleen, kidney, and pancreas, and the least persistent in heart and liver. The AUC for 7-OMEN in organs was the greatest in lungs (605 nmol/g X hr), spleen (522 nmol/g X hr), and pancreas (430 nmol/g X hr), and least in heart (33 nmol/g X hr) and liver (60 nmol/g X hr). Kidneys and skeletal muscles had intermediate AUC values. In liver, two metabolites, one of which had the HPLC characteristics of N- demethylmenogarol , were seen. In other organs, the same metabolites were seen later and in small quantities.

Animals↗
PubMed1983

Comparative genotoxicity of adriamycin and menogarol, two anthracycline antitumor agents.

Adriamycin and menogarol are anthracyclines which cause more than 100% increase in life span of mice bearing P388 leukemia and B16 melanoma. Unlike Adriamycin, menogarol does not bind strongly to DNA, and it minimally inhibits DNA and RNA synthesis at lethal doses. Adriamycin is a clinically active drug, and menogarol is undergoing preclinical toxicology at National Cancer Institute. In view of the reported mutagenicity of Adriamycin, we have compared the genotoxicity of the two drugs. Our results show that, although Adriamycin and menogarol differ significantly in their bacterial mutagenicity (Ames assay), they have similar genotoxic activity in several mammalian systems. Adriamycin is strongly mutagenic in the Ames assay with TA98 and TA100. Menogarol is nonmutagenic to TA98 and TA100. For the mammalian cell culture systems, V79 (Chinese hamster) cells are exposed for 2 hr to drug, following which cell survival, induction of sister chromatid exchanges, chromosome damage, and production of mutants resistant to 6-thioguanine are measured. The percentage of survival obtained with the two drugs ranges between 25 and 50% at 0.15 microgram/ml and 5 to 15% at 0.3 microgram/ml. At 0.15 microgram/ml, Adriamycin and menogarol increase the percentage of cells with chromosome damage from a background level of 8.8 to 30 and 22.5%, respectively. The same drug concentration causes a small but significant increase in sister chromatid exchange rate. Both drugs are equally active (increase mutation frequency about 3- to 6-fold above background) in producing 6-thioguanine-resistant mutants. The induction of micronuclei in polychromatic erythrocytes of rats is the most sensitive assay system. Both drugs cause 10- to 15-fold increase in micronuclei at nontoxic doses.

Animals↗
PubMed1981

Effect of 7-con-O-methylnogarol on DNA synthesis, survival, and cell cycle progression of Chinese hamster ovary cells.

The effect of 7-con-O-methylnogarol (7-OMEN) on the survival of exponentially growing and plateau-phase Chinese hamster ovary cells was determined in a cloning assay. After 2 hr of exposure, the 50% lethal dose for exponential and plateau-phase cells was 0.3 and 1.5 microgram/ml, respectively. Drug doses for cell progression studies were based upon drug lethality; therefore, higher doses were used for plateau than for exponential populations. The effect of 7-OMEN on cell progression was studied by DNA flow cytometry under the following conditions: (a) during 24 hr of continuous exposure of exponentially growing cells; (b) during recovery of exponential cells after 2 or 7 hr of drug exposure; and (c) during recovery of plateau-phase cells after 2 hr of exposure. Exponential cells exposed continuously for 24 hr progressed normally from M to G1 phase and from G1 to S phase, progression through S phase was slowed, and cells were ultimately blocked in G2 + M. Inhibition of S-phase progression was dose dependent, 0.2 microgram/ml having only slight effect and 1.0 microgram/ml accumulating a large fraction in S phase. Inhibition of S-phase progression correlated with DNA synthesis inhibition. Similar inhibitory effects were observed after pulsed (2- or 7-hr) exposure of exponential cells. 7-OMEN also blocked plateau-phase cells in G2 + M after 2 hr of exposure, but higher doses (3.0 microgram/ml) were required. Simultaneous exposure of exponential cells to Colcemid (which blocks cells in metaphase) and 1.0 microgram 7-OMEN per ml completely inhibited the expected increase in mitotic index, indicating that the G2 + M block observed by DNA flow cytometry was a block in G2 or prophase.

Animals↗
PubMed1993

[New anthracyclines].

Idarubicin showed the superior activity against Acute Non-Lymphocytic Leukemia (ANLL) in the prospective randomized trials comparing to daunorubicin and it is judged that the analog will become the first choice in the treatment on ANLL. Anthracyclines including SM-5887, KRN-8602, ME-2303 under studies in Japan have shown comparable or superior antitumor activities and lower cardiac toxicities compared to doxorubicin in preclinical studies and therefore the results obtained in clinical trials are expected. Phase II trials of anthrapyrazoles which is an analog of mitoxantrone are in progress. Among three compounds entered it is of note that CI-941 has demonstrated an excellent activity against advanced breast cancer.

Animals↗