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R C Jackson

Publications and source records attributed to R C Jackson.

At least 37 records · Page 2Linked to original sources
PubMed1993

Inhibition of 5-phosphoribosyl-1-pyrophosphate synthetase by the monophosphate metabolite of 4-amino-8-(beta-D-ribofuranosylamino)pyrimido[5,4-d]pyrimidine: a novel mechanism for antitumor activity.

The aminopyrimidopyrimidine nucleoside 4-amino-8-(beta-D-ribofuranosylamino)pyrimido[5,4-d]pyrimidine (APP), which was previously shown to possess experimental antitumor and antiviral activity, was metabolized within WI-L2 human lymphoblastoid cells to a derivative identified as the beta-D-ribonucleotide (APP-MP). In a subline of WI-L2 cells deficient in adenosine kinase, this metabolite was not formed and APP was not cytotoxic, suggesting that APP is converted by adenosine kinase to its 5'-monophosphate. Because no evidence of di- or triphosphates was seen, the monophosphate appeared to be the active species. Treatment of WI-L2 or L1210 cells with APP (10 microM) for 30 min caused extensive depletion of both purine and pyrimidine ribonucleotides. Purine and pyrimidine deoxyribonucleotides were also depleted. Cells were not protected from the cytotoxicity of APP by hypoxanthine plus uridine, but uridine plus adenosine plus 2-deoxycoformycin gave considerable protection. This result was consistent with APP-MP acting as an inhibitor of 5-phosphoribosyl-1-pyrophosphate (PRPP) synthetase, a hypothesis that was confirmed by preparing PRPP synthetase from Novikoff hepatoma cells; APP-MP was a noncompetitive inhibitor, with a Ki of 0.43 mM. APP-MP was found to accumulate in APP-treated cells to a concentration of almost 3 mM. The relevance of PRPP synthetase inhibition to the cytotoxic mechanism of APP is indicated by the fact that depletion of the PRPP pool was seen as early as 15 min after treatment, before any change was apparent in cellular levels of ATP or UTP. DNA synthesis was markedly suppressed within 30 min of APP treatment of WI-L2 cells, and a lesser degree of inhibition of RNA synthesis was apparent after 45 min.

Animals↗
PubMed1990

Calcium- and guanine-nucleotide-dependent exocytosis in permeabilized rat mast cells. Modulation by protein kinase C.

We have used a digitonin-permeabilized cell system to study the signal transduction pathways responsible for stimulus-secretion coupling in the rat peritoneal mast cell. Conditions were established for permeabilizing the mast cell plasma membrane without disrupting secretory vesicles. Exocytotic release of histamine from digitonin-permeabilized cells required a combination of micromolar concentrations of Ca2+ and the stable guanine nucleotide analogue guanosine 5'-[gamma-thio]triphosphate (GTP[S]), but was independent of exogenous ATP. In the presence of 40 microM-GTP[S], exocytosis was half-maximal at 1.3 microM-Ca2+ and maximal at 10 microM-Ca2+; GTP[S] alone (100 microM) had no effect on histamine release in the absence of added Ca2+. In the presence of 10 microM free Ca2+, 5 microM-GTP[S] was required for half-maximal exocytosis. To examine the possible role of protein kinase C (PKC) in exocytosis, we utilized 12-O-tetradecanoylphorbol 13-acetate (TPA) to activate PKC and studied its effect on histamine release from permeabilized mast cells. Cells that had been incubated with TPA (25 nM for 5 min) exhibited increased sensitivity to both GTP[S] and Ca2+. The PKC inhibitor staurosporine blocked the effect of TPA without inhibiting normal exocytosis in response to the combination of GTP[S] and Ca2+. In addition, down-regulation of mast-cell PKC by long-term TPA treatment (25 nM for 20 h) blocked the ability of the cells to respond to TPA and inhibited exocytosis in response to Ca2+ and GTP[S] by 40-50%. These results suggest that the sensitivity of the exocytotic machinery of the mast cell can be altered by PKC-catalysed phosphorylation events, but that activation of PKC is not required for exocytosis to occur.

Animals↗
PubMed1990

Immunolocalization of hyalin in sea urchin eggs and embryos using an antihyalin-specific monoclonal antibody.

Monoclonal antibodies were raised against purified cortical secretory vesicles (CVs) from the eggs of Strongylocentrotus purpuratus. One of the monoclonal antibodies (MAb 69-10, an IgA) was shown by immunofluorescence labeling of intact and detergent-lysed CVs to be directed against a CV content antigen. Immunoblot analysis of CVs revealed that MAb 69-10 bound to a major CV polypeptide with an Mr similar to that of hyalin (i.e., 300,000). MAb 69-10 was subsequently shown to bind to purified hyalin prepared from S. purpuratus and to cross react with hyalin prepared from Lytechinus pictus. Immunogold labeling on thin sections of unfertilized S. purpuratus eggs showed that hyalin was localized to the electron-lucent portion of CVs. This result is in agreement with the labeling pattern obtained by Hylander and Summers (Dev Biol 93:368-380, 1982) using polyclonal antihyalin antibodies. In fertilized eggs and later-stage embryos, hyalin was observed to be located on the external surface of the embryo. MAb 69-10 should be useful in studies of the structure of hyalin and its function in morphogenesis.

Animals↗
PubMed1990

Reassociation of cortical secretory vesicles with sea urchin egg plasma membrane: assessment of binding specificity.

An assay has been developed for quantitating the reassociation of cortical secretory vesicles (CVs) with fragments of sea urchin egg plasma membrane attached to glass slides (PM lawns). Binding of S. pupuratus CVs to homologous PM lawns increased with time and CV concentration. The observation that CV binding was blocked by chymotrypsin digestion of the PM fragments suggested that a PM protein(s) is required for reassociation. The possibility that the extent of CV lysis that occurred during CV preparation (15.4 +/- 3.8% as assessed by ovoperoxidase assay) influenced reassociation was investigated by determining the effect of CV content proteins (isolated as fertilization product) on binding. Various concentrations of fertilization product (up to equivalent amounts of fertilization product and CV protein) had no effect on CV binding. The specificity of binding was investigated by assessing the ability of CVs to bind to PM lawns prepared from human red blood cells, and by determining the ability of heterologous vesicles to bind to egg PM fragments. PM lawns from HRBCs did not support CV binding; however, PM lawns prepared from the eggs of several species of sea urchin did bind S. pupuratus CVs. Vesicles from a partially purified preparation of yolk platelets bound to egg PM lawns with low efficiency (1/7 that of CVs), but immunofluorescence analysis with an anti-hyalin monoclonal antibody demonstrated that 74 +/- 9% of the bound vesicles were CVs that contaminated the yolk platelet preparation. Dioleoylphosphatidyl choline liposomes were also unable to bind to egg PM lawns. These results are consistent with hypothesis that CV binding to egg PM lawns is a specific, protein-mediated event.

Animals↗
PubMed1990

N-ethylmaleimide-sensitive protein(s) involved in cortical exocytosis in the sea urchin egg: localization to both cortical vesicles and plasma membrane.

The exocytotic release of secretory products from fragments of sea urchin egg cortex has been shown to be inhibited by covalent modification of membrane sulfhydryl groups with N-ethylmaleimide (NEM). Exocytotically competent preparations of reconstituted cortex, formed by recombination of purified cortical vesicles (CVs) with fragments of egg plasma membrane (PM) were also inhibited by treatment with NEM. The cellular localization of sulfhydryl-containing constituent(s) responsible for inhibition was investigated by treating CVs and/or PM with NEM prior to reconstitution. Both native cortex and cortex reconstituted with NEM-treated components were challenged with calcium-containing buffers. Exocytosis was monitored by phase-contrast microscopy, and quantitated by light scattering. Evidence for CV-PM fusion was obtained with an immunofluorescence-based assay that permits visualization of the transport of CV content proteins across the PM. Cortex reconstituted by recombination of NEM-treated CVs with untreated PM or by recombination of untreated CVs with NEM-treated PM was exocytotically competent, whereas cortex formed by recombination of NEM-treated CVs with NEM-treated PM was inactive. These results: (1) support the hypothesis that the mechanism of exocytosis in native and reconstituted cortex is the same; (2) provide evidence that both CV and plasma membranes participate in the release of CV contents from reconstituted cortex; and (3) suggest that sulfhydryl-containing protein(s) present on the surface of purified CVs and plasma membrane are involved in exocytosis.

Animals↗
PubMed1989

Purification and characterization of a cortical secretory vesicle membrane fraction.

A membrane fraction has been prepared by sucrose density gradient fractionation of purified cortical secretory vesicles from the eggs of the sea urchin Strongylocentrotus purpuratus. The purified cortical vesicle membrane fraction has a phospholipid to protein ratio of 1.76 and exhibits a morphology typical of biological membranes as seen by electron microscopy. The protein composition of the purified membranes was analyzed by SDS-polyacrylamide gel electrophoresis and shown to be distinct from that of eggs, cell surface complex, cortical vesicles, fertilization product, and yolk platelets. Alkaline extraction (pH 11.0) of peripheral membrane proteins increased the phospholipid to protein ratio to 2.55 and removed several polypeptides. Immunoblot analysis of the isolated cortical vesicle membrane fraction revealed low levels of contamination with two major cortical vesicle content proteins. Fractions enriched in egg plasma membranes and yolk platelet membranes also have been isolated and compared with the cortical vesicle membranes by SDS-polyacrylamide gel electrophoresis. The protein compositions of the three membrane fractions were found to contain very little overlap, indicating that the cortical vesicle membrane preparation is relatively free of contamination from these likely noncortical vesicle sources of membrane. Both the plasma membrane and cortical vesicle membrane samples were found by immunoblotting to contain actin.

Actins↗
PubMed1989

Identification of a major polypeptide component of the sea urchin fertilization envelope.

A monoclonal antibody (MAb No. 25-16), raised against purified cortical secretory vesicles (CVs) from the eggs of Strongylocentrotus purpuratus, has been used to identify a previously uncharacterized CV-derived polypeptide component of the sea urchin fertilization envelope (FE). MAb No. 25-16, an IgG1, bound to a group of proteins with Mr approximately 200,000 on immunoblots of CVs. This same group of proteins also was detected in fertilization product and in soft FEs prepared from early embryos, indicating that the antigen is released at fertilization by CV exocytosis and becomes incorporated into the FE. The multiple components recognized by MAb No. 25-16 apparently did not result from proteolysis during sample preparation or differential N-linked glycosylation. No simplification of the SDS-gel or immunoblot patterns was observed when samples of fertilization product or cell surface complex were prepared in the presence of a cocktail of protease inhibitors; nor was a change in mobility of any of the antigen forms detected following treatment with endoglycosidase F. Upon partial denaturation and reduction of the protein by incubation at room temperature in the presence of SDS and dithiothreitol, the antigen was shown to undergo a decrease in relative mobility on SDS-PAGE. Complete reduction and denaturation, by boiling in dithiothreitol-containing SDS sample buffer or by an on-blot reduction technique, resulted in loss of the epitope. The protein component recognized by MAb No. 25-16 underwent a striking increase in mobility on SDS-PAGE after chelation of calcium ions with EGTA. Immunogold labeling on thin sections of unfertilized eggs revealed that the antigen is located in the spiral lamellar cores of all CVs. In fertilized eggs, fixed 5 min after insemination, the antigen was detected in the FE. Based on these biochemical and immunological data, we suggest that the antigen recognized by MAb No. 25-16 is released exocytotically from the CVs into the perivitelline space at fertilization and becomes incorporated into the FE. The abundance of this antigen suggests that it may function as a structural component of the FE.

Animals↗
PubMed1989

Biochemical pharmacology and antitumor properties of 4-amino-8-[beta-D-ribofuranosylamino]pyrimido-[5,4-d]pyrimidine.

1. APP is activated by adenosine kinase to its 5'-phosphate (APP-MP). 2. APP-MP inhibits PRPP synthetase, and depletes cellular PRPP and purine and pyrimidine nucleotides. 3. APP inhibits synthesis of DNA and RNA, and blocks cells in G1 phase of the cell cycle. 4. APP retains full activity against MDR cells. 5. APP is equally active against quiescent and proliferating CHO cells. 6. APP has only weak activity against L1210 leukemia in vivo, but has substantial activity against mammary carcinoma 16/c. 7. In vitro, APP has a relatively high ratio of solid tumor: leukemia activity.

Animals↗
PubMed1989

The problem of the quiescent cancer cell.

1. Antimetabolites and inhibitors of DNA topoisomerase II are relatively ineffective against quiescent cells. 2. Alkylating agents (carmustine, cisplatin) retain significant activity against Q-cells. 3. Of the various cytokinetic reasons why tumors may have slow growth rates (long cycle times, high cell loss factors, differentiation, Q-cells), modeling studies suggest that the presence of a large Q-cell compartment has the most serious implications for chemotherapy. 4. Agents may be active against Q-cells for two reasons: (a) Direct cytotoxicity that is not dependent upon cell proliferation, e.g., direct DNA damage or ATP depletion. (b) Drug accumulation and retention within the cells, resulting in delayed cytotoxicity when the cell re-enters the cell cycle. 5. Q-cells have low rates of RNA synthesis, very low rates of DNA synthesis, and relatively normal ribonucleotide pools. Though earlier results suggest that RNA synthesis is an exploitable target for Q-cell cytotoxic agents, the RNA synthesis inhibitor NSC 366140 did not inhibit RNA synthesis in Q-cells. 6. The pyrazoloacridine, NSC 366140, retained a high level of activity against quiescent cells, as did other pyrazoloacridine compounds with a 9-methoxy substitution. 7. Successful chemotherapy of carcinomas with high Q-fractions will probably require the development of new Q-cell active drugs with sites of action other than DNA. The antimetabolite APP-MP is an example of a non-DNA-directed agent active against Q-cells.

Animals↗
PubMed1988

Inhibition of type II topoisomerase by fostriecin.

Fostriecin is a new antitumor antibiotic which is being developed further as an anticancer agent based on its marked activity in murine leukemias. Its mechanism of action, however, has thus far remained unknown. The present study demonstrates that fostriecin inhibits the catalytic activity of partially purified type II topoisomerase from Ehrlich ascites carcinoma. Under the experimental conditions employed, fostriecin completely inhibited the enzyme at 100 microM. A general kinetic analysis showed that fostriecin inhibited topoisomerase in an uncompetitive manner with a Ki,app of 110 microM and produced kinetics that were distinctly different from those of VM-26 which exhibited noncompetitive inhibition. Fostriecin did not cause DNA strand breaks in L1210 cells, suggesting that it did not stabilize a cleavable complex as do other known inhibitors of this enzyme. Fostriecin, however, did partially inhibit DNA strand breaks produced by amsacrine. An analysis by flow cytometry showed that L1210 cells exposed to 5 microM fostriecin for 12 hr caused a block in the G2 phase of the cell cycle. These studies thus suggest that the mechanism by which fostriecin produces its antitumor effects may be through inhibition of topoisomerase II and that the type of inhibition is markedly different from existing antitumor agents which inhibit this enzyme.

Adenosine Triphosphate↗
PubMed1988

Enzymic and Photosynthetic Characteristics of Reciprocal F(1) Hybrids of Flaveria pringlei (C(3)) and Flaveria brownii (C(4)-Like Species).

The activities of key C(4) enzymes in gel-filtered, whole-leaf extracts and the photosynthetic characteristics for reciprocal F(1) hybrids of Flaveria pringlei (C(3)) and F. brownii (C(4)-like species) were measured to determine whether any inherited C(4)-photosynthetic traits are responsible for their reduced CO(2) compensation concentration values (AS Holaday, S Talkmitt, ME Doohan Plant Sci 41: 31-39). The activities of phosphoenolpyruvate carboxylase, pyruvate, orthophosphate dikinase, and NADP-malic enzyme (ME) for the reciprocal hybrids are only about 7 to 17% of those for F. brownii, but are three- to fivefold greater than the activities for F. pringlei. The low activities of these enzymes in the hybrids appear to be the result of a partial dominance of F. pringlei genes over certain F. brownii genes. However, no such dominance occurs with respect to the expression of genes for NADP-malate dehydrogenase, which is as active in the hybrids as in F. brownii. In contrast to the situation with the enzymes above, cytoplasmic factors appear to determine the inheritance of NAD-ME. The NAD-ME activity in each hybrid is comparable to that in the respective maternal parent. Pulse-chase (14)CO(2) incorporation analyses at ambient CO(2) levels indicate that the hybrids initially assimilate 7 to 9% of the total assimilated CO(2) into C(4) acids as compared to 3.5% for F. pringlei. In the hybrids, the percentage of (14)C in malate decreases from an average of 6.5 to 2.1% after a 60-second chase in (12)CO(2)/air. However, this apparent C(4)-cycle activity is too limited or inefficient to substantially alter CO(2) exchange from that in F. pringlei, since the values of net photosynthesis and O(2) inhibition of photosynthesis are similar for the hybrids and F. pringlei. Also, the ratio of the internal to the external CO(2) concentration and the initial slopes of the plot of CO(2) concentration versus net photosynthesis are essentially the same for the hybrids and F. pringlei. At 45 micromoles CO(2) per mole and 0.21 mole O(2) per mole, the hybrids assimilate nearly fivefold more CO(2) into C(4) acids than does F. pringlei. Some turnover of the malate pool occurs in the hybrids, but the labelling of the photorespiratory metabolites, glycine and serine, is the same in these plants as it is in F. pringlei. Thus, although limited C(4)-acid metabolism may operate in the hybrids, we conclude that it is not effective in altering O(2) inhibition of CO(2) assimilation. The ability of the hybrids to assimilate more CO(2) via phosphoenolpyruvate carboxylase at low levels of CO(2) than does F. pringlei may result in an increased rate of reassimilation of photorespiratory CO(2) and CO(2) compensation concentrations below that of their C(3) parent. If the hybrids do possess a limited C(4) cycle, it must operate intracellularly. They are not likely to have inherited an intercellular compartmentation of C(4) enzymes, since F. brownii has incomplete compartmentation of key C(3) and C(4) enzymes.

Journal Article↗
PubMed1987

Pyrazoloacridines, a new class of anticancer agents with selectivity against solid tumors in vitro.

A series of 2-aminoalkyl-5-nitropyrazolo[3,4,5-kl]acridines (pyrazoloacridines) was evaluated in vitro for activity against a panel of human tumor cell lines of breast, colon, or lung origin. Several pyrazoloacridines were found to possess solid tumor selectivity relative to their activity against murine leukemia L1210 cells as well as human lymphoblastoid cells. The superior compounds in this regard were also found to exhibit excellent activity against primary human tumors in stem cell clonogenic assays. In addition, many of the compounds tested were found to be selectively cytotoxic to hypoxic relative to oxic HCT-8 colon adenocarcinoma cells, a property that may be a consequence of the potentially reducible 5-nitro function. A number of pyrazoloacridines were also found to exhibit potency against noncycling Chinese hamster ovary cells comparable to that observed against actively dividing cultures. Consistent with their favorable activity against nondividing cells, further testing of the pyrazoloacridines revealed that generally less drug is required to inhibit RNA synthesis than DNA synthesis in L1210 cells. Collectively these data indicate that the pyrazoloacridines represent a novel class of antitumor agents which warrant further preclinical evaluation for their potential clinical usefulness in the treatment of solid tumors.

Acridines↗
PubMed1987

Biological and biochemical properties of new anticancer folate antagonists.

We review the biology and biochemical pharmacology of four antifolates that were recently introduced into clinical trial as anticancer agents, and one compound in preclinical development. Toxicology and clinical data are not discussed. 10-Ethyl-10-deazaaminopterin (10-EdAM) is a classical antifolate, structurally related to methotrexate (MTX) but with greater activity against murine tumors. 10-EdAM has more efficient membrane transport, and relatively greater polyglutamylation in murine tumors than in normal mouse tissues, and these differential effects are greater for 10-EdAM than for other 10-deaza antifolates or for MTX. Trimetrexate and piritrexim are nonclassical antifolates, lacking a glutamate substitution. They are lipophilic, cross cell membranes more rapidly than does MTX, and retain activity against tumors resistant to MTX because of impaired drug transport. These nonclassical antifolates are active against several MTX-insensitive murine tumors, and both have demonstrated clinical anticancer activity. 10-EdAM, trimetrexate and piritrexim all inhibit dihydrofolate reductase (DHFR) as their primary site of action. As such, they deplete cellular thymidylate and purine pools, and inhibit DNA replication. N10-Propargyl-5,8-dideazafolic acid (CB3717) differs from the first three compounds in acting primarily on thymidylate synthase. Like DHFR inhibitors, it blocks DNA replication through depletion of dTTP, but it does not exert an antipurine effect. CB3717 retains activity against transport-defective MTX-resistant cells, and also against cells that overproduce DHFR. 5,10-Dideazatetrahydrofolic acid (DDATHF) is a selective inhibitor of glycinamide ribotide transformylase, and its biochemical pharmacology may differ appreciably from that of the other antifolates under study. DDATHF has strong antitumor activity in several murine systems.

Animals↗
PubMed1987

In vitro reconstitution of exocytosis from sea urchin egg plasma membrane and isolated cortical vesicles.

We have succeeded in reconstituting an exocytotically active egg cortex fraction by recombining purified cortical vesicles (CVs) with egg plasma membrane (PM). CVs were dislodged from a suspension of egg cortex by gentle homogenization in a dissociative buffer with a pH of 9.1, and purified by two rounds of differential centrifugation. Egg PM was prepared by shearing the cortical vesicles from a cortical lawn preparation with a jet of isotonic buffer. PM lawns produced by this procedure consist of an array of CV-free PM fragments attached via their extracellular surface to a polylysine coated glass slide. When a neutralized suspension of CVs was recombined with a PM lawn, CVs reassociated with the cytoplasmic face of the plasma membrane to form a reconstituted lawn (RL). RLs undergo a morphological change in response to Ca2+-containing buffers that is similar to the exocytotic release of CV contents from cortical lawns. In both reactions CV contents are vectorially transferred from the cytoplasmic to the extracytoplasmic face of the egg PM. A quantitative binding assay was developed and used to show that adherence of CVs to a heterologous PM lawn prepared from human red blood cells is minimal.

Animals↗
PubMed1987

Biochemical pharmacology and experimental chemotherapy studies with guanine-7-oxide, a novel purine antibiotic.

1. Guanine-7-oxide is a novel purine antibiotic produced by a Streptomyces species, ATCC 39364. 2. Guanine-7-oxide is cytotoxic to murine and human leukemia cells in vitro at sub-micromolar concentrations. Murine and human carcinoma cells are much less sensitive. 3. Guanine-7-oxide has significant in vivo antitumor activity, particularly against the intraperitoneal and subcutaneous L1210 leukemia systems. 4. Guanine-7-oxide, at highly cytotoxic concentrations, has little effect on biosynthesis of RNA and DNA. 5. There is preliminary evidence for an early effect of guanine-7-oxide on cellular protein synthesis. 6. Guanine, guanosine and hypoxanthine protect cells from the cytotoxicity of guanine-7-oxide. 7. Activation of guanine-7-oxide requires the presence of the enzyme hypoxanthine-guanine phosphoribosyltransferase in the target cells. 8. Cytotoxic concentrations of guanine-7-oxide do not cause depletion of cellular guanine nucleotides during a two hr incubation period. 9. Guanine-7-oxide is converted within mouse and human cells to a metabolite with chromatographic mobility corresponding to a ribonucleoside 5'-triphosphate.

Animals↗
PubMed1987

Anthrapyrazole anticancer agents. Synthesis and structure-activity relationships against murine leukemias.

Chromophore modification of the anthracenediones related to mitoxantrone in an attempt to provide agents with diminished or no cardiotoxicity has resulted in a novel class of DNA binders, the anthrapyrazoles. Their synthesis was carried out by a two-stage condensation sequence starting from requisite 1,4- or 1,5-dichloro-9,10-anthracenedione precursors. Reaction with a monoalkylhydrazine gave a chloroanthrapyrazole intermediate whose subsequent condensation with primary or secondary alkylamines provided the target "two-armed" anthrapyrazoles. A-ring 7,10-dihydroxy anthrapyrazoles were derived from amine condensation with intermediate 5-chloro-7,10-dihydroxyanthrapyrazoles or, alternatively, from intermediate 5-chloro-7,10-bis(benzyloxy)anthrapyrazoles followed by hydrogenolysis of the benzyl protecting groups to provide the target compounds. Potent in vitro activity was demonstrated against murine L1210 leukemia in vitro (IC50 = 10(-7)-10(-8) M) as well as against P388 leukemia in vivo over a wide range of structural variants. In general, activity against the P388 line was maximized by basic side chains at N-2 and C-5, two to three carbon spacers between proximal and distal nitrogens of the side chain, and A-ring hydroxylation. Besides having curative activity against the P388 line, the more active compounds were curative against murine B-16 melanoma in vivo. On the basis of their exceptional in vivo anticancer activity, A-ring dihydroxy compounds 71 and 74 reported in this study have been selected for development toward clinical trials.

Animals↗