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Insertions and deletions (indels) are common in intergenic spacer regions of plastid DNA and can provide important phylogenetic characters for closely related species. For example, a 241-bp plastid DNA deletion in the trnV-UAC/ndhC intergenic spacer region has been shown to have major phylogenetic importance in determining the origin of the cultivated potato. As part of a phylogenetic study of the wild potato Solanum series Piurana group we screened 199 accessions of 38 wild potato species in nine of the 19 tuber-bearing ( Solanum section Petota) series that have not been examined before for indels in the trnV-UAC/ ndhC intergenic spacer region. A novel 41 bp deletion (but no 241 bp deletion) was discovered for 30 accessions of three species: S. chiquidenum (5 of 10 accessions), S. chomatophilum (19 of 28), and S. jalcae (6 of 6). Accessions with and without this deletion are found throughout much of the north-south range of all three species in northern and central Peru, but not east of the Marañón River. Multivariate morphological analyses of these 44 accessions showed no morphological associations to the deletion. The results suggest extensive interspecific gene flow among these three species, or a common evolutionary history among species that have never been suggested to be interrelated. [ABSTRACT FROM AUTHOR]

A 2 x 4 x 4factorial design was used to assess the effects of physical attractiveness in a domestic violence case. The attractiveness of both the defendant and victim were varied along four levels. Subjects were asked to read a domestic violence scenario where pictures of the defendant and victim were varied according their physical attractiveness. Results showed no significant effect of physical attractiveness in a juridic decision-making process in domestic violence. However, there were significant differences between male and female subjects in the sentencing of the defendant. This difference did not hold true for finding the defendant guilty or not guilty. [ABSTRACT FROM AUTHOR]

This paper presents the case of a 51-year-old man with a ganglion originating from the superior tibiofibular joint. In the context of the present literature, different theories of the pathogenesis, clinical symptoms, various kinds of imaging methods in regard of the differential diagnosis and the broad spectrum of operative and non-operative treatment are discussed. [ABSTRACT FROM AUTHOR]

Pharmacokinetics of the experimental antitumor agent indicine N-oxide were investigated in a group of 23 pediatric cancer patients. Plasma elimination of indicine N-oxide was best described by a two-compartment open model. The mean plasma distribution phase half-life, plasma elimination phase half-life, and plasma clearance were 8 min, 84 min, and 62 ml/min/m2 (2.1 ml/min/kg), respectively. One patient with renal impairment had an abnormally long plasma elimination phase half-life (275 min) and reduced plasma clearance (17 ml/min/m2). Plasma elimination phase half-life values increased and plasma clearance values decreased with increasing age of the pediatric patients. Plasma elimination of indicine N-oxide was more rapid in this group of children than in adults who had previously received the drug. [ABSTRACT FROM AUTHOR]

Plasma and urine concentrations of amygdalin, whole-blood concentrations of cyanide, and thiocyanate concentrations in serum and urine were determined in cancer patients following intravenous (4.5 g/m2) and oral (500-mg tablet) administration of amygdalin. To measure low plasma concentrations of amygdalin following oral administration a GC/MS assay was developed. Following intravenous administration, concentrations of parent drug as high as 1,401 microgram/ml were observed, with no increase in plasma concentrations of cyanide or serum concentrations of thiocyanate. Plasma elimination of amygdalin was best described by a two-compartment open model with a mean distributive phase half-life of 6.2 min, mean elimination phase half-life of 120.3 min, and mean clearance of 99.3 ml/min. Following oral administration of amygdalin, plasma concentrations were much lower, with peak values of less than 525 ng/ml. Cyanide concentrations increased to values as high as 2.1 microgram/ml whole blood. Thiocyanate concentrations did not increase for several days, plateauing at values as high as 38 microgram/ml serum. Ingestion of almonds by two patients taking oral amygdalin increased cyanide concentrations compared with values obtained after oral amygdalin alone. [ABSTRACT FROM AUTHOR]

Dose-dependent pharmacokinetics have been reported more frequently for anticancer drugs than for other drugs, probably because anticancer drugs are studied over a wide range of doses during early evaluation and because of the increasing use of anticancer drugs at very high doses. Dose-dependent pharmacokinetics are reflected most commonly as an increase in the biological half-life of a drug and a greater than proportional increase in plasma concentration of the drug and in area under the drug concentration-time curve with increase in dose. Occasionally the rate of drug removal increases with increasing dose. These nonlinear changes in drug concentrations with dose may lead to increases in toxicity out of proportion to increases in dose. Appreciation of the possibility of dose-dependent pharmacokinetics is important in the clinical pharmacologic evaluation of new drugs, and may be essential for the design of effective therapeutic regimens. [ABSTRACT FROM AUTHOR]

Ecteinascidins are marine natural products with potent antiproliferative activity under evaluation as chemotherapeutic agents by the National Cancer Institute. Ecteinascidins bind the minor groove of DNA and may form covalent adducts with DNA by binding the N-2 of guanine in a fashion similar to saframycin antibiotics. The most potent ecteinascidin is ET-729 with antitumor activity observed following administration of 3.8 and 10 μg/kg to mice bearing P388 leukemia and B16 melanoma, respectively. A reverse-phase high-performance liquid chromatography (HPLC) assay and an L1210 cell bioassay were developed for ET-729 and utilized for stability and murine pharmacokinetic studies. HPLC analysis showed that ET-729 was stable in organic solvents, mobile phase and acidic buffer (t > 100 h). Stability was diminished under neutral and basic conditions (t < 14 h). Following a 48-h incubation with L1210 cells in growth medium in the absence and presence of 2.5% murine plasma, the 50% growth inhibitory concentrations (IC) of ET-729 were 37 and 72 p M, respectively. Following intravenous administration of ET-729 to male CD2F mice, the disappearance of antiproliferative activity determined by the bioassay was described by a two-compartment open model. The mean values of the elimination half-life and plasma clearance were 28 min and 39.7 ml/min per kg, respectively. Following intraperitoneal administration, peak plasma concentrations of antiproliferative activity were observed 6-15 min after injection and antiproliferative concentrations remained above 1 n M for longer than 1 h. Intraperitoneal bioavailability varied over a wide range (20-91%). Antiproliferative activity was detected in every urine sample following intravenous and intraperitoneal administration, but the total 48-h urinary recovery was less than 0.1%. [ABSTRACT FROM AUTHOR]

The anthracycline analog idarubicin (ID) is useful in the treatment of leukemias, and is of further interest because of the unique activity of its major circulating metabolite idarubicinol (IDOL). In vitro studies have shown that ID retains activity against tumor cells made resistant by prolonged exposure to substrates of the p-glycoprotein energy-dependent efflux pump. To selectively investigate multidrug resistance to ID in tumor cells, ID, IDOL, doxorubicin (DX) and doxorubicinol (DXOL) were evaluated for growth inhibitory activity when incubated with NIH-MDR1-G185 (MDR) cells or with the parent NIH-3T3 (3T3) cells. The MDR cells are transfected with the human multidrug gene mdr1, and express a functional p-glycoprotein. ID growth inhibitory activity was much less affected by p-glycoprotein-mediated efflux than was DX. ID IC50 values were only 1.8-fold greater in the MDR cell line than in the parental 3T3 cell line, while the IC50 value for DX was 12.3-fold greater in the transfected cell line. Verapamil (VRP) fully restored drug sensitivity of the MDR cell line to ID and DX. In studies with the alcohol metabolites, IDOL and DXOL IC50 values were 7.8- and 18.9-fold greater, respectively, for the MDR cell line than for the parental cell line. Intracellular concentrations of DX and DXOL, but not ID and IDOL, were substantially increased in the MDR cells when VRP was present in the incubation mixtures. ID and IDOL retain substantial growth inhibitory activity in mdr1-transfected cells, and ID may be of value in clinical settings where multidrug resistance mediated by p-glycoprotein is a potential limitation of therapy. [ABSTRACT FROM AUTHOR]

Cholera toxin was selected for pharmacologic evaluation by the National Cancer Institute on the basis of antiproliferative activity against small-cell and non-small-cell lung-cancer cell lines. A feature common to the sensitive cell lines was abundant expression of GM1 ganglioside, the cellular receptor for cholera toxin. A sandwich enzyme-linked immunosorbent assay (ELISA) was developed to quantitate cholera toxin in biological fluids. A sigmoidal relationship was observed between the cholera toxin plasma concentration and the absorbance at 490 nm (OD490) of the product of horseradish peroxidase-catalyzed oxidation of o-phenylenediamine over the range of 6.25-1,600 ng/ml. Logit transformation of the OD490 data was linear over the entire concentration range and assay variability was less than 25%. Cholera toxin was stable in murine and human whole blood and plasma. Following i.v. administration of 1,500 micrograms/kg to male CD2F1 mice, cholera toxin plasma elimination was described by a two-compartment open model. The half-lives (t1/2 alpha, t1/2 beta), plasma clearance, and steady-state volume of distribution were 0.7 min, 49 min, 24 ml min-1 kg-1 912 ml/kg, respectively. Cholera toxin was not detected in plasma following an s.c. dose of 1,500 micrograms/kg. Urinary recovery following intravenous drug administration was less than 0.1%. [ABSTRACT FROM AUTHOR]

Bizelesin (NSC-615291), a potent, bifunctional analog of the cyclopropylpyrroloindole antitumor antibiotics CC-1065 and adozelesin, has been selected by the National Cancer Institute for evaluation as a potential chemotherapeutic agent. All three compounds bind to and alkylate DNA at the N-3 position of adenine in a sequence-selective manner. Bizelesin is unique among the analogs with bifunctional alkylating capability due to two chloromethyl moieties that are converted to the cyclopropyl alkylating species that interact with DNA. A reverse-phase high-performance liquid chromatography (HPLC) assay and an L1210 cell bioassay were developed for bizelesin and subsequently applied to stability and murine pharmacokinetics studies. Following 48 h of incubation with L1210 cells the 50% growth-inhibitory concentrations (IC50) of bizelesin, adozelesin, and CC-1065 were 2.3, 3.4, and 88.1 pM, respectively. Bizelesin was stable in organic solvents but was less stable in aqueous solutions, with the half-life values obtained in buffers at pH 4, 7, and 10 being 9.6, 2.1, and < 1 h, respectively. By HPLC analysis, bizelesin degradation was associated with the appearance of two peaks, the mono- and dicyclopropyl derivatives formed by base-catalyzed intramolecular alkylation of the chloromethyl groups. Bizelesin and the dicyclopropyl derivative were equipotent in the L1210 cell bioassay. Following i.v. administration of bizelesin (15 micrograms/kg) to male CD2F1 mice, the plasma elimination of cytotoxic activity determined with the bioassay was described by a two compartment open model; the alpha-phase (t1/2 alpha) and beta-phase (t1/2 beta) half-lives, steady-state volume of distribution (VSS), and total body clearance (ClTB) were 3.5 min, 7.3 h, 7,641 ml/kg, and 16.3 ml min-1 kg-1, respectively. The systemic drug exposure following i.p. administration was at least 10 times lower than that resulting from i.v. infusion. Following i.v. or i.p. administration the recovery of material in urine was < 0.1% of the delivered dose. [ABSTRACT FROM AUTHOR]

Anthracyclines are important antitumor agents used in the treatment of solid tumors, lymphomas, and acute lymphoblastic as well as myelocytic leukemias. The clinical utility of agents such as doxorubicin and daunorubicin and their well-characterized cardiotoxicity have prompted many efforts to develop analogs that retain the desired spectrum of activity but are less cardiotoxic. One such analog is idarubicin (4-demethoxydaunorubicin), which is currently under study in the treatment of adult and pediatric leukemias. The major circulating metabolite of idarubicin is the alcohol product of ketoreductase biotransformation, idarubicinol. Following the administration of idarubicin to adult or pediatric patients, systemic exposure to idarubicinol is greater than that to idarubicin. Moreover, we have also documented the presence of idarubicinol in the cerebrospinal fluid of pediatric patients who have received idarubicin. Idarubicinol has been reported to have greater cytotoxic activity than other anthracycline alcohol metabolites, which are regarded as much less active products of metabolism. We therefore evaluated the growth-inhibitory and DNA-damaging activities of idarubicin, daunorubicin, doxorubicin, epirubicin, and their alcohol metabolites against three relevant (CCRF-CEM lymphoblastic leukemia, K562 myelogenous leukemia, and U87-MG glioblastoma) human tumor cell lines. We found that whereas idarubicin was 2-5 times more potent than the other three anthracycline analogs against these tumor cell lines, idarubicinol was 16-122 times more active than the other alcohol metabolites against the same three cell lines. In addition, idarubicinol and the parent drug idarubicin were equipotent, unlike the other anthracycline alcohol metabolites, which were much less cytotoxic than the corresponding parent drugs. We also assessed the ability of the four parent drugs and their alcohol metabolites to induce DNA single-strand breaks. Idarubicin was more potent than the other three anthracycline analogs and idarubicinol was much more effective than the other alcohol metabolites in inducing DNA damage. These studies in human leukemia and human glioblastoma cell lines support the hypothesis that idarubicinol plays an important role in the antitumor activity of idarubicin and that the activities of idarubicin and idarubicinol are related to their ability to damage DNA. [ABSTRACT FROM AUTHOR]

Oxantrazole (now designated as piroxantrone) is an anthrapyrazole analog under evaluation as a potentially useful anthracycline-like antitumor agent. In preparation for phase I clinical trials, we characterized certain aspects of oxantrazole preclinical pharmacology, including plasma stability, murine pharmacokinetics, in vitro/in vivo metabolism, and DNA damage following incubation with human tumor cells in culture. Oxantrazole was relatively unstable in fresh mouse and dog plasma and particularly unstable in fresh human plasma (t 1/2 less than 5 min at 37 degrees C). Its decomposition in plasma was prevented by the addition of ascorbic acid, suggesting oxidative degradation. Following rapid i.v. administration of oxantrazole to mice, plasma elimination was best described by a two-compartment open model with an elimination-phase half-life, total body clearance, and steady-state volume of distribution of 330 min, 458 ml/min per m2, and 87.9 l/m2, respectively. The c x t value calculated following i.v. administration of 90 mg/m2 oxantrazole to mice was 177 micrograms-min/ml. This value was subsequently used in a pharmacologically guided dose-escalation scheme for the oxantrazole phase I clinical trial. Oxantrazole was converted to a polar conjugate, presumably a beta-glucuronide, by rat but not mouse hepatic microsomal preparations and in vivo by the mouse. Oxantrazole introduced protein-associated DNA strand breaks following incubation with a human rhabdomyosarcoma cell line. Repair of the damage was complete by 15 h. Clinical pharmacologic studies are currently under way in conjunction with the phase I clinical trial of oxantrazole. [ABSTRACT FROM AUTHOR]

Incubation of hexamethylmelamine for 1 h with human tumor cell lines in culture did not inhibit colony formation at concentrations up to the limit of drug solubility (200 micrograms/ml). When 1-h incubations were carried out in the presence of a 9,000 g rat liver supernatant preparation and an NADPH-generating system, hexamethylmelamine markedly reduced colony formation. Cyclophosphamide inhibition of colony formation was also dependent on the presence of a 9,000 g supernatant preparation and an NADPH-generating system in incubation mixtures. A 1-h incubation of N-methylolpentamethylmelamine (a DNA-alkylating metabolite formed during N-demethylation of hexamethylmelamine) with human tumor cell lines reduced colony formation in the absence of the liver-activating system. Substantial NADPH-dependent N-demethylation of hexamethylmelamine was observed with rat liver, lung, and kidney microsomal preparations. In contrast, little or no HMM metabolism was observed with tumor cells, tumor cell homogenates, or NADPH-fortified tumor cell microsomal preparations. NADPH-dependent formation of cytotoxic metabolites is a prerequisite for antiproliferative activity of hexamethylmelamine against these human tumor cell lines. In vivo activity of hexamethylmelamine against some tumors may require metabolism by normal cells and subsequent transport of active species to the tumor site. [ABSTRACT FROM AUTHOR]

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