Carcinostatic Activity Research Articles

The Antitumor Activity of Ginger against Colorectal Cancer Induced by Dimethylhydrazine in Rats.

Bowl or colorectal cancer (CRC) is the third most common type of cancer with about two million new cases every year. CRC is the second leading cause of cancer related mortalities. The study aims to evaluate the anticancer activity of ethanolic Ginger Extract (GE) in HCT-116 colon cells and colorectal tumors induced by dimethylhydrazine (DMH). The antiproliferative activity was measured by MTT assay and the gene expression was assessed by q-RTPCR. For the antitumor study, rats were divided into five groups in random; control, group two was orally treated with 300 mg/kg of GE for 21 weeks, group three was s.c. injected with DMH (20 mg/kg) for 9 weeks, and groups four and five were treated with DMH and then treated with cisplatin (2.5 mg/kg, i.p) or GE, respectively, for 21 weeks. GE had a significant antiproliferative activity with IC50~ 12.5 µg/ml. GE induced both extrinsic and intrinsic apoptotic pathways. GE induced the expression of FasL, TRAIL, p53, and caspase-8 and downregulated Bcl-2 and survivin genes. Treatment of rats with DMH resulted in 100% tumor incidence and 2.3 tumors/rat. DMH significantly elevated the serum ALT, urea, and creatinine and significantly decreased the body weight gain. DMH also caused significant reductions in the hepatic GSH level, and the activities of catalase, SOD, GST, and GR in the liver as well as the renal GSH content and γ-GT activity. The colon from rats insulted with DMH showed adenomatous polyps with polymorphism and mitosis. The mucosa and submucosa were infested with inflammatory cells while serosa and muscularis were devoid from these cells. However, the muscularis was infiltrated with cystic formation, anaplastic changes, and hemorrhage. GE was able to alleviate all the previous deleterious effects of DMH and it was superior to cisplatin in its ameliorative effects. It did so without eliciting hepatotoxicity or nephrotoxicity which were shown in the group treated with DMH and cisplatin. This study proved that the antitumor activity of GE against the DMH induced-CRC is superior to cisplatin. GE was also safer than cisplatin and did not elicit hepatotoxicity or nephrotoxicity. GE induced apoptosis and has carcinostatic activity.

Synthesis, Characterization and Thermal Studies of Cr (III), Co (II) and Ni (II) Complexes with Schiff Base

The physiologically active compounds of Schiff bases find application in the treatment of several diseases. This biological activity of Schiff base is attributed to the formation of stable chelates with a transition metal, and they are known to exhibit a wide variety of pharmacological properties and carcinostatic activities. Cr (III), Co (II), and Ni (II) complexes of Schiff base were chosen for the present experimental work and theoretical treatment and characterized by different spectroscopies such as elemental analysis CHN, infrared, ultra visible spectroscopies, magnetic susceptibility, molar conductivity measurements, and thermal analysis The results of this research, indicate that the complexes have a type composition [M (NL)]. Schiff base NL: derived from 2-aminobenzoic acid and Benzil, M: Cr (III), Co (II), and Ni (II) transition metal ions. Schiff base acts as a tetradentate ligand with ions through the hydroxyl groups and imine groups. The work was included theoretical calculations of NL and its complexes, which were done by the program of hyperchem8. 0.7 using semi-empirical calculations. The PM3 method used to calculate the heat of formation (ΔH○f), binding energy (ΔEb), total energy (ΔEtot), and geometric properties of the compounds.

Dietary Compounds for Targeting Prostate Cancer.

Prostate cancer is the third most common cancer worldwide, and the burden of the disease is increased. Although several chemotherapies have been used, concerns about the side effects have been raised, and development of alternative therapy is inevitable. The purpose of this study is to prove the efficacy of dietary substances as a source of anti-tumor drugs by identifying their carcinostatic activities in specific pathological mechanisms. According to numerous studies, dietary substances were effective through following five mechanisms; apoptosis, anti-angiogenesis, anti-metastasis, microRNA (miRNA) regulation, and anti-multi-drug-resistance (MDR). About seventy dietary substances showed the anti-prostate cancer activities. Most of the substances induced the apoptosis, especially acting on the mechanism of caspase and poly adenosine diphosphate ribose polymerase (PARP) cleavage. These findings support that dietary compounds have potential to be used as anticancer agents as both food supplements and direct clinical drugs.

CRet Systemによるハイパーサーミア併用 低LET放射線のがん抑制効果

CRet Systemによるハイパーサーミア併用 低LET放射線のがん抑制効果

Novel Nicotinonitrile Derivatives Bearing Imino Moieties Enhance Apoptosis and Inhibit Tyrosine Kinase.

Fused heterocyclic containing pyrazolopyridine systems have several medicinal activities including cytotoxic and carcinostatic activities. To investigate the antiproliferative activity and associated mechanism(s) of a novel series of nicotinonitrile derivatives. The series has been synthesized by the reaction of hydrazonoyl chlorides with each of 4-(4- methoxyphenyl)-3-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and 2-amino-4-(4- methoxyphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile in dioxane in basic medium. The assigned structures for each of the new products were identified via elemental and spectral data. Moreover, the cytotoxic activity for some selected products was screened. Derivatives 5g, 7i, 8 and 9 had their IC50 at ~ 1-3 µM and derivatives 7b, 7d, and 7f were similar to 5- fluorouracil and had their IC50 at ~ 5 µM against breast (MCF-7) and colon (HCT-116) cell lines. All derivatives were specific in action and safe to normal fibroblasts (WI38). Only derivative 9 caused some toxicity but at high concentration of 93 µM. These derivatives exerted strong antiproliferative activity through inducing intrinsic apoptosis as indicated from the significant induction of caspases 9 and 3 by 3-6 folds in colon cells and/or inhibiting tyrosine kinase (TK) and hence arresting the cell cycle. Compounds 8 and 5g were the most potent anticancer agents inhibiting the TK by 86 and 89% and their IC50 of the enzyme were 311 and 352 nM, respectively. We believe that these derivatives deserve further investigation and these chemical moieties could offer promising anticancer drugs.

A methoxyflavanone derivative from the Asian medicinal herb (Perilla frutescens) induces p53-mediated G2/M cell cycle arrest and apoptosis in A549 human lung adenocarcinoma.

Perilla frutescens is an Asian dietary herb consumed as an essential seasoning in Japanese cuisine as well as used for a Chinese medicine. Here, we report that a newly found methoxyflavanone derivative from P. frutescens (Perilla-derived methoxyflavanone, PDMF; 8-hydroxy-5,7-dimethoxyflavanone) shows carcinostatic activity on human lung adenocarcinoma, A549. We found that treatment with PDMF significantly inhibited cell proliferation and decreased viability through induction of G2/M cell cycle arrest and apoptosis. The PDMF stimulation induces phosphorylation of tumor suppressor p53 on Ser15, and increases its protein amount in conjunction with up-regulation of downstream cyclin-dependent kinase inhibitor p21Cip1/Waf1 and proapoptotic caspases, caspase-9 and caspase-3. We also found that small interfering RNA knockdown of p53 completely abolished the PDMF-induced G2/M cell cycle arrest, and substantially abrogated its proapoptotic potency. These results suggest that PDMF represents a useful tumor-preventive phytochemical that triggers p53-driven G2/M cell cycle arrest and apoptosis.

Carcinostatic effects of diverse ascorbate derivatives in comparison with aliphatic chain moiety structures: Promotion by combined hyperthermia and reduced cytotoxicity to normal cells

In this study, using human tongue squamous carcinoma cells (HSC-4) carcinostatic activity was compared for diverse L-ascorbic acid (Asc) derivatives, including the 'straight-C(16)-chain types', 6-O-palmitoyl-Asc (A6-P) and Asc-2-phosphate-6-O-palmitate sodium salt (APPS), as well as the 'branched-C(16)-chain types', Asc-2-phosphate-6-O-(2'-hexyl)decanoate (APHD), an isomer of APPS, and Asc-2,3,5,6-O-tetra-(2'-hexyl)decanoate (VCIP). The order of magnitude of the carcinostatic effects at 37°C was: APPS>A6-P = APHD>VCIP and at 42°C was APPS = A6-P>APHD>VCIP. Therefore, the two straight-C(16)-chain derivatives, APPS and A6-P, had a greater effect compared to the two branched-C(16)-chain Asc derivatives, which are considered to have more difficulty with 'orientation along cell-membrane-glycerolipid direction'. APPS-treated HCS-4 cells were observed for a decrease in cell number, cell shrinkage, pycnosis indicative of apoptosis and cell deformation. The order of cytotoxicity for the normal human dermal fibroblasts (OUMS-36) at 37°C was: A6-P (50% inhibitory concentration: 150-300 μM)>APHD (450-600 μM)>>Asc = APPS (800-1000 μM). Accordingly, APHD was more cytotoxic than APPS, since the straight-C(16)-chain type, which was eliminated after the enzymatic esterolysis of APPS, is metabolized via the 'fatty acid β-oxidation cycle' more efficiently in normal cells. Thus, APPS had a greater advantage over APHD, A6-P and VCIP in terms of carcinostatic effects at 37°C, carcinostasis promotion at 42°C and a decrease of cytotoxicity to normal cells. This observation suggests a marked potential for aliphatic chain-moiety structures as anticancer agents, due to their cancer-selective carcinostasis and combined efficacy with hyperthermia, without causing side effects.

Antitumor and anti-invasive effects of diverse musk-fragrant macrocyclic ketones and their enhancement by hyperthermia

The antitumor and anti-invasive activities of the low-molecular-weight macrocyclic ketones (MCKs), such as musk secreted from the mammalian genital glands and musk released from relatively unkown plants, were investigated comparatively together with the enhancement of the effects in combination with hyperthermia. Ehrlich ascites tumor cells were treated with each MCK and cultured, followed by evaluation of the cell viability using the mitochondrial dehydrogenase-based WST-8 assay. The number of HT-1080 human fibrosarcoma cells cultured with the MCKs or invading through a reconstituted basement membrane was measured using microscopy. The order of the efficiency was as follows: (Z)-g-cycloheptadecen-1-one (Hp) (17:1, musk rats), 8-cyclohexadecen-1-one (16:1, musk ferns), cyclopentadecanone (15:0, musk rats) and 3-methylcyclopentadecanone (16:0, musk deer), having 15-17 carbon atoms with and without a double bond, which exhibited a carcinostatic effect either at 100 µM for 20-h culture or at 50 µM for 72-h culture. The effects were markedly enhanced by heat treatment at 42˚C. MCKs were not found in the cells by gas-liquid chromatographic determination, indicating that the carcinostatic effects were attributed to their surface activity on the cell membrane. Invasion of HT-1080 cells was inhibited by MCKs at doses scarcely diminishing the cell viability, indicating that the suppression of invasiveness did not ensue from the secondary action due to carcinostasis. The order of invasion-inhibitory efficacy of the MCKs was, however, similar to that of their carcinostatic effects. Hp17:1 also exhibited the highest anti-invasive activity in addition to the highest carcinostatic activity. The two inhibitory effects were promoted by combination with hyperthermia. MCKs with a double bond, particularly Hp17:1 rather than 8-Hx16:1, but not saturated-aliphatic MCKs, may be potent multi-applicable antitumor agents due to their dual inhibitory activities against tumor progression and invasion and in hyperthermia-combined therapy.

Chemical and clinical development of darinaparsin, a novel organic arsenic derivative.

The inorganic arsenic derivative arsenic trioxide (ATO) has proven to be highly efficacious in patients with acute promyelocytic leukemia (APL) and has been associated with complete cytogenetic response in most treated patients diagnosed with this disease. This is due to ATO's direct effect on PML-RARalpha oncoprotein patognomonic for APL. ATO has shown moderate activity against certain other hematologic and solid organ malignancies but is also associated with significant toxicities, especially when used at higher doses. The development of orally bioavailable organic arsenic derivatives (OAD) offering improved toxicity profiles and better efficacy may expand the use of arsenic derivatives in hematologic malignancies and solid tumors. The favorable in vivo carcinostatic activity of S-dimethylarsino-thioglucose, the first OAD synthesized in murine leukemia models by our group in 1975, set the stage for our efforts to develop OADs. Unfortunately, the program remained dormant for almost two decades. The success of ATO in APL in the late 1990s re-ignited the interest in the use of OADs in cancer chemotherapy. This review describes the chemical development of OADs and summarizes the clinical development of a promising lead compound, Darinaparsin (ZIO-101; SGLU; S-dimethylarsino-glutathione), for the treatment of a variety of cancers.

The antitumor activities of the structurally-similar two-species aromatics Tonalide and Pearlide and the enhancement of their effects by hyperthermia

Antitumor activities have been reported for the aromatics Tonalide (6-acetyl-1,1,2,4,4,7-hexamethyl-tetrahydronaphthalene, AHTN) and Pearlide (1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethyl-cyclopenta-γ-2-benzopyran, HHCB), which are contained in detergents. In this study, their carcinostatic activities in Ehrlich ascites tumor (EAT) cells were evaluated by mitochondrial dehydroganase-based WST-1 assay and dye-exclusion assay. The viability of EAT cells treated at 37 or 42°C for 30 min and sequentially cultured at 37°C was assayed at graded times. Immediately after treatment at 37°C, neither Tonalide nor Pearlide had an effect on EAT cells, even at a concentration as high as 200 µM. However, cell viability was reduced to 40% versus the control after 20 h of culture with Tonalide at 50 µM, and to below 20% at 25 µM after 72 h. In contrast, Pearlide was nearly inactive, even at a dose of 100 µM after 20 h of culture, and only reduced cell viability to 41.2% after 72 h. After treatment at 42°C without culture, neither of the aromatics was effective, even at a dose of 200 µM. The viability of cells cultured with Tonalide for 20 h after treatment at 42°C was reduced to nearly half of that at 37°C, and to 10% of the control after culture for 72 h. These values for the reduction of cell viability were also acheived by the Trypan blue dye-exclusion assay. The lifespan-prolonging effects of Tonalide on mice implanted with EAT cells were also examined. The lifespan of mice administrated 1.8 mg/day of Tonalide was prolonged by up to 28 days, while mice that did not receive Tonalide died within a mean of 15 days. Thus, Tonalide exhibited marked carcinostatic effects in vitro and in vivo and may prove to be a potent multipurpose antitumor agent in combination with hyperthermia.

Caffeic acid phenethyl ester induces mitochondria-mediated apoptosis in human myeloid leukemia U937 cells

Caffeic acid phenyl ester (CAPE), a biologically active ingredient of propolis, has several interesting biological properties including antioxidant, anti-inflammatory, antiviral, immunostimulatory, anti-angiogenic, anti-invasive, anti-metastatic and carcinostatic activities. Recently, several groups have reported that CAPE is cytotoxic to tumor cells but not to normal cells. In this study, we investigated the mechanism of CAPE-induced apoptosis in human myeloid leukemia U937 cells. Treatment of U937 cells with CAPE decreased cell viability in a dose-dependent and time-dependent manner. DNA fragmentation assay revealed the typical ladder profile of oligonucleosomal fragments in CAPE-treated U937 cells. In addition, as evidenced by the nuclear DAPI staining experiment, we observed that the nuclear condensation, a typical phenotype of apoptosis, was found in U937 cells treated with 5 microg/ml of CAPE. Therefore, it was suggested that CAPE is a potent agent inducing apoptosis in U937 cells. Apoptotic action of the CAPE was accompanied by release of cytochrome C, reduction of Bcl-2 expression, increase of Bax expression, activation/cleavage of caspase-3 and activation/cleavage of PARP in U937 cells, but not by Fas protein, an initial mediator in the death signaling, or by phospho-eIF2 alpha and CHOP, crucial mediators in ER-mediated apoptosis. From the results, it was concluded that CAPE induces the mitochondria-mediated apoptosis but not death receptors- or ER-mediated apoptosis in U937 cells.

Antitumor and anti-invasive effects of diverse new macrocyclic lactones, alkylolides and alkenylolides, and their enhancement by hyperthermia

Alkylolides and alkenylolides of 198-254 Da such as hexadecan-16-olide and 9-hexadecen-16-olide were chemically synthesized in the present study as new macrocyclic lactones that are structurally different from widespread natural macrocyclic lactones including bryostatin (887 Da) and rhizoxin (613 Da), and were investigated for antitumor activity to Ehrlich ascites tumor cells by mitochondrial dehydroganase-based WST-1 assay and dye-exclusion assay. Of the alkylolides having 12, 15 or 16 carbon-atoms (D12:0, P15:0 or H16:0) and alkenylolides having 15 or 16 carbon-atoms with a double bond (P15:1 or H16:1), H16:0 was the most carcinostatic when administered at 37 degrees C for 20 h, with cell deformation and microvillus disappearance as detected by scanning electron microscopy. The carcinostatic activity was increased markedly for H16:0 and P15:0 when the administration period was prolonged to 72 h, but was not enhanced by intramolecular introduction of a double bond for P15:1 or H16:1. Hyperthermia at 42 degrees C for 30 min additively intensified the carcinostatic activity for H16:0 and P15:0, but scarcely for D12:0, and intensified the alkenyloides P15:1 and H16:1 only upon the subsequent 72-h treatment. Invasion of human fibrosarcoma HT-1080 cells through the reconstituted basement membrane was inhibited by alkyl- and alkenylolides even after the short-term exposure at 25 microM for 3 h without diminishing the cell viability. H16:0 also exhibited the most inhibitory activity to tumor invasion in addition to the highest carcinostatic activity. Both inhibitions were promoted by combination with hyperthermia. Thus diverse alkyl-/alkenylolides, may be potent multi-applicable anticancer agents in terms of either dual inhibitory activities against both tumor progression and invasion or hyperthermia-combined therapy.

Anti-tumor and anti-invasive effects of diverse delta-alkyllactones: Dependence on molecular side-chain length, action period and intracellular uptake

New delta-alkyllactones (DALs) with diverse side-chain lengths (184–254 Da), which are structurally different from the widespread, naturally occurring delta-lactones of higher molecular weight (348–439 Da), such as camptothecin and sultriecin, were chemically synthesized and analyzed for their carcinostatic activity. Of the DALs with 11, 12, 13, 14, or 16 carbon atoms, delta-hexadecalactone (DH16:0) was the most carcinostatic when administered to Ehrlich ascites tumor (EAT) cells at 37 °C for 20 h, and measured by the mitochondrial dehydrogenase-based WST-1 assay. Prolongation of the administration period to 72 h enhanced the carcinostatic activity more markedly for DH16:0 than for other DALs. The carcinostatic activity of DALs was unexpectedly augmented by increasing the number of carbon atoms, in contrast to the conventional view that carcinostatic activity is attenuated by the addition of carbon atoms to fatty acids. Intracellular accumulation of DH16:0, as analyzed by gas chromatography, was detected (1.5 Pg/cell), whereas other DALs studied were rarely found. The results indicate a close relationship between carcinostatic activity and intracellular accumulation. Invasion of human fibrosarcoma HT-1080 cells through the reconstituted basement membrane was inhibited by several DALs, even at doses as low as 5–10% of those necessary for carcinostatic activity, suggesting an invasive mechanism different from carcinostasis. The invasion–inhibitory activity was intensified by increasing the number of carbon atoms, in a manner similar to that for the carcinostatic activity. The lifespan of EAT-cell-transplanted mice was markedly prolonged with DH16:0, presumably due to excellent distribution throughout the body and tumor cells. Thus DH16:0 may be a potent anticancer agent, in term of its carcinostatic, anti-invasive, and lifespan-prolonging activities.

Oxidation of glutathione and superoxide generation by inorganic and organic selenium compounds

The carcinostatic activities of selenium (Se) compounds have been shown to be composition and concentration dependent. Several studies have indicated that the ratios between glutathione (GSH) and Se may play an important role in Se catalysis and toxicity. The present study examined the catalytic effect of three selenium compounds on GSH oxidation using lucigenin-dependent chemiluminescence (CL) as an indirect measure of superoxide generation. Various GSH:Se ratios were assayed for the glutathione oxidase activity of selenite, selenocystamine and diselenodipropionic acid. CL emitted from the reaction of selenite with GSH increased more rapidly and was greater than those from the diselenides, but the diselenide CL reactions were sustainable. Both selenite- and diselenide-induced CL were markedly suppressed by superoxide dismutase (SOD). Iodoacetic acid (IAc) effectively inhibited CL generated from selenite-, selenocystamine- and diselenodipropionic acid-catalyzed GSH oxidation. These results suggest that GSH oxidation catalyzed by selenite, and the diselenides selenocystamine and diselenodipropionic acid, generated the superoxide radical in which the CL was inhibited by SOD. Furthermore, CL inhibition by IAc suggests that the catalytic species producing superoxide were the GSSe(-) or RSe(-) anion. This redox chemistry may be responsible for selenite and organoselenium toxicity and apoptosis, making possible the design and synthesis of organoselenium-containing pharmaceuticals.

Enhancement of carcinostatic activity of ω-hydroxy fatty acids by their esterification through increased uptake into tumor cells

Diverse omega-hydroxy fatty acids (omegaHFAs) and their derivatives were examined for their ability to diminish the cell viability of Ehrlich ascites tumor cells by the mitochondrial dehydrogenase-based WST-1 assay and trypan blue dye exclusion assay. Of the diverse omegaHFAs, hydroxyhexadecanoic acid (omegaH16:0) was appreciably carcinostatic, and hydroxypentadecanoic acid (omegaH15:0) or hydroxypentadecenoic acid (omegaH15:1) was weakly carcinostatic at a dose of 100 micro M, whereas hydroxydodecanoic acid (omegaH12:0) and hydroxyhexadecenoic acid (omegaH16:1) acid were scarcely carcinostatic at the same dose. In contrast their sodium salt derivatives except omegaH16:0 were not carcinostatic. Enhancement of the carcinostatic activity was markedly exerted by ethylesterization of omegaHFAs with the saturated fatty moiety such as omegaH16:0 and omegaH15:0, whereas ethylesters of the unsaturated omegaHFAs such as omegaH15:1 and omegaH16:1 were weakly carcinostatic. Thus intramolecular introduction of a double bond was shown to weaken the carcinostatic activity in case of either omegaHFAs or their ethylester, being in contrast to the conventional knowledge concerning the enhancement of carcinostatic activities of non-hydroxy fatty acids appendant with more double bonds. The intracellular uptake amount of each omegaHFA as quantified by gas chromatography was the following order: omegaH16:0 ethylester (10.1 pg/cell) > omegaH15:0 ethylester (6.4 pg/cell) > omegaH16:0 (3.4 pg/cell) > omegaH15:0 (2.8 pg/cell), which accords with the order of carcinostatic activities of four saturated omegaHFAs in contrast to discord between both the orders for unsaturated omegaHFAs which could be scarcely detected as the intact form within cells. The results indicate that enhancement of carcinostatic activity of omegaH16:0 by ethylesterization was attributed to an appreciable correlation between intracellular uptake amounts and carcinostatic activities for diverse omegaHFAs with saturated fatty moiety, being not true for unsaturated omegaHFAs.

Methioninase and selenomethionine but not Se-methylselenocysteine generate methylselenol and superoxide in an in vitro chemiluminescent assay: implications for the nutritional carcinostatic activity of selenoamino acids

Methylselenol from selenium metabolism is postulated to be and most experimental evidence now indicates that it is the selenium metabolite responsible for the dietary chemoprevention of cancers. Using the recombinant enzyme methioninase, methylselenol-generating chemiluminesence by superoxide (O 2 −) is shown to be catalytically produced from l-selenomethionine and d, l-selenoethionine, but not from methionine or l-Se-methylselenocysteine (SeMC). Methylselenol enzymaticaly generated by methioninase activity from the substrate selenomethionine arises from an initial putative selenium radical as measured by chemiluminesence in the absence of glutathione (GSH). In the presence of GSH, superoxide was generated as measured by chemiluminesence and superoxide dismutase inhibition of chemiluminescence. Ascorbic acid also quenched the chemiluminesence from the activity of methioninase with selenomethionine. Methylselenol and other redox cycling selenium compounds are almost assuredly accountable for inducing cell-cycle arrest and apoptosis in cancer cells in vitro and in vivo. Methylselenol generated from selenomethionine by methioninase is catalytic alone in oxidizing thiols, i.e. GSH, generating superoxide and inducing oxidative stress in direct proportion to its concentration. Se-methylselenocysteine in vivo is very likely carcinostatic in like manner to selenomethionine by generating methylselenol from other enzymatic activity, i.e. beta-lyase or amino acid oxidases.

Carcinostatic, protective, and adaptive activities of tris-(2-hydroxyethyl)ammonium salts of arylheteroacetic acids.

Carcinostatic, protective, and adaptive activities of tris-(2-hydroxyethyl)ammonium salts of arylheteroacetic acids.

Correlation of DNA synthesis-inhibiting activity and the extent of transmembrane permeation into tumor cells by unsaturated or saturated fatty alcohols of graded chain-length upon hyperthermia.

The carcinostatic activity has been studied for fatty acids of diverse species but scarcely for fatty alcohols. Three unsaturated fatty alcohols at 35-50 microM inhibited DNA synthesis and the proliferation of tumor cells by a combination with hyperthermia to greater extents in the order: oleyl (C18:1)-> linoleyl (C18:2)-> alpha-linolenyl (C18:3) alcohol, which is an order inverse to that known for the corresponding fatty acids (4). In contrast, two saturated fatty alcohols, palmityl (C16:0)- and stearyl (C18:0) alcohols, did not inhibit at the same concentrations. At 100 microM, palmityl alcohol inhibited, whereas stearyl alcohol did not. The effective fatty alcohols appreciably permeated the cells. The inhibition of the unsaturated fatty alcohols on DNA synthesis and proliferation was nearly proportional to the amount of their intercellular accumulation at 37 degrees C or 42 degrees C; the most inhibitory, oleyl alcohol, was the most membrane-permeable, whilst inversely the least inhibitory, alpha-linolenyl alcohol, was the least permeable. A proportional correlation was not observed for saturated fatty alcohols; palmityl alcohol underwent an approximate 2-fold more abundant accumulation than other fatty alcohols, but was weakly inhibitory. Thus, oleyl alcohol may exert an antitumor action via appropriately efficient transmembrane permeation and a combination with hyperthermia.

A quadruply-bonded dirhenium complex bridged by two N 1/N 6 adenate ligands

The first structurally characterized example of a metal-metal bonded complex bridged by the DNA nucleobase adenine through the N1, N6 positions is reported. The new dirhenium compound, Re 2(O 2CCH 2CH 3) 2(9-EtA) 2Cl 2 · CH 3CH 2O · C 6H 14, binds to adenine at the sites where thymine normally engages in Watson-Crick base-pairing. Such chemistry, if it occurs in vivo, could play a role in the carcinostatic activity of tetrapropionatodirhenium complexes that are known to inhibit DNA replication.

Structural Evidence for a New Metal-Binding Mode for Guanine Bases: Implications for the Binding of Dinuclear Antitumor Agents to DNA

A central theme in bioorganic chemistry is the investigation of transition metal anti-tumor compounds, particularly those of the platinum group elements. Certain dinuclear metal complexes are known to exhibit carcinostatic activity, but unlike cis-platin, the mechanism of action is not well understood. Previous binding studies of Rh{sub 2}(O{sub 2}CCH{sub 3}){sub 4} with various nucleosides and nucleotides led to claims that only adenine bases are capable of forming complexes. This paper presents evidence from model studies with 9-ethylguanine, guanosine and the dinucleotides d(GpGp) and d(GpG) that support an alternative binding mode for dinuclear complexes with DNA base. Reactions of Rh{sub 2}(O{sub 2}CR{sub 3}){sub 4} and [Ru{sub 2}(O{sub 2}CR{sub 3}{sub 4}{sup +} with guanosine and 9-ethylguanine support the formation of novel products of general formula [M{sub 2}(O{sub 2}CR{sub 3}){sub 2}(purine){sub 2}]{sup 2+}]. An x-ray structure of [Rh{sub 2}(O{sub 2}CCF{sub 3}){sub 2}(9-ethyl-guanine)){sub 2}]{sup 2+} revealed an unprecendented bridging N7-06 interaction for 9-ethylguanine in the complex. In related studies, Rh{sub 2}(O{sub 2}CCF{sub 3}){sub 4} undergoes facile complex formation with d(GpGp) and d(GpG) to yield products whose properties closely resemble those of the purine and nucleoside compounds. Results of molecular mechanics calculations, {sup 1}H NMR and electronic spectroscopies, fast atom bombardment mass spectrometry (FAB-MS) andmore » crystallography are presented to support these conclusions.« less