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PubMed1984

Heterogeneity of infection enhancement of dengue 2 strains by monoclonal antibodies.

Seven dengue (DEN) 2 virus strains were studied for antibody-dependent enhancement (ADE) of infection in P388D1 mouse macrophage-like cells by using a panel of five DEN 2 monoclonal antibodies. DEN 2 strains were of diverse temporal, geographic, and disease origins. By hemagglutination inhibition and a plaque-reduction neutralization test in LLC-MK2 cells, two of the monoclonal antibodies were type specific and three were flavivirus group reactive. In LLC-MK2 cells, the seven DEN 2 viruses each were neutralized by all five monoclonal antibodies. In P388D1 cells, two DEN 2 strains were enhanced by only three monoclonal antibodies, two by four antibodies, and three by all five antibodies, demonstrating that in some instances enhancement is epitope related and not a concentration-dependent function of virus-antibody interactions. However, ADE did not segregate with determinants exhibiting either the flavivirus group or the dengue type specificity. The presence or absence of enhancement determinants on DEN 2 strains did not correlate with the geographic origin of virus or the severity of disease yielding the strain. The heterogeneous distribution of enhancement determinants may provide a valence mechanism contributing to a multiple increase of infection enhancement in macrophages.

Animals↗

PubMed1994

Changes of monoamines, purines and amino acids in rat striatum as measured by intercerebral microdialysis during ischemia/reperfusion.

The aim of this study was to determine the time course of changes in extracellular fluid (ECF) concentrations of purines, amino acids, monoamines, and their metabolites in the striatum of rats during ischemia and reperfusion, using intracerebral microdialysis as the sampling technique. In rats subjected to 20 min forebrain ischemia by four-vessel occlusion, the concentrations of adenosine (Ade), inosine (Ino) and hypoxanthine (Hyp) were found to rise markedly. These changes were accompanied by dramatically elevated levels of aspartate (Asp), glutamate (Glu), taurine (Tau), gamma-aminobutyric acid (GABA), dopamine (DA) and norepinephrine (NE), all of which gradually returned to baseline following reperfusion. Concomitantly, the levels of metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindole-3-acetic acid (5-HIAA) and xanthine (Xan) decreased during ischemia and gradually recovered 60-90 min after reperfusion. It was concluded that during global brain ischemia, the ECF is flooded with both potentially harmful (e.g. Asp, Glu, DA) and protective (e.g. Tau, GABA, Ade) agents.

Amino Acids↗

PubMed1993

Transcription of genes encoding granulocyte-macrophage colony-stimulating factor, interleukin 3, and interleukin 6 receptors and lack of proliferative response to exogenous cytokines in nonhematopoietic human malignant cell lines.

Studies in recent years have suggested that human tumor cell lines are capable of responding in vitro to hematopoietic growth factors. In the present study, we investigate the transcription of the alpha and beta subunits of granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor, the alpha and beta subunits of interleukin 3 (IL-3) receptor, and the single subunit of interleukin 6 (IL-6) receptor and its associated gp130 transduction protein by PCR amplification of reverse-transcribed cellular mRNA in 34 malignant cell lines derived from a variety of histological cell types. mRNA for only a single subunit polypeptide was found in a significant minority of cell lines (23%), while in 20% both the alpha and beta subunits of either the GM-CSF receptor or the IL-3 receptor were detected among a number of different histological cell types. Transcription of the gene encoding the IL-6 receptor was found in 38% of cell lines, and all lines transcribed the gp130 transduction protein, consistent with previous observations on the ubiquity of that polypeptide. In order to test the in vitro effect of exogenously added growth factors on those malignant cell lines transcribing complete cytokine receptor, either GM-CSF, IL-3, or IL-6 was added in therapeutic concentrations (20-500 ng/ml) and cellular proliferation was measured by incorporation of [3H]thymidine. No stimulation was seen at either 3 and 6 days of culture. Production of cytokine by these cell lines was investigated at the level of transcription and by assay of peptide product. None transcribed mRNA for either GM-CSF or IL-3, while 5 of 6 (STD, DOZ, ADE, Hep-2, and Detroit) expressed IL-6 mRNA. Of these latter, 2 cell lines (ADE and Hep-2) produced IL-6 as determined by bioassay, while none produced GM-CSF or IL-3 by enzyme-linked immunosorbent assay. This suggests that in the case of GM-CSF and IL-3, failure to proliferate on addition of cytokine is not due to the prior presence of endogenous production. In contrast, at least a subset of malignant cell lines may involve a closed IL-6 autocrine loop saturating cell surface sites. These findings suggest that the ability to transcribe the genes encoding cytokine receptor is by itself insufficient to render cells cytokine responsive and that malignant cells may lack the cellular machinery for cytokine-induced proliferation. This in turn suggests that therapeutic administration of either GM-CSF, IL-3, or IL-6 may involve no additional risk of tumor regrowth in vivo.

Base Sequence↗

PubMed1993

Complement and virus-specific antibody-dependent infection of normal B lymphocytes by human immunodeficiency virus type 1.

We tested the susceptibility of human purified, normal B lymphocytes to human immunodeficiency virus type 1 (HIV-1) infection, in the presence or absence of complement-sufficient serum and of virus-specific antibodies. Virus replication was detected when cells were infected in the presence of both complement and anti-HIV antibodies (C'-ADE conditions), by day 2 postinfection. Similar results were obtained when B lymphocytes were purified either from peripheral blood (three healthy donors) or from tonsils (four individuals with chronic tonsillitis). HIV infection was shown by polymerase chain reaction (PCR) detection of proviral sequences (gag and pol genes), by p24 antigen synthesis, and by cocultivation assay with MT2 cells. The higher p24 production was obtained when B cells were preactivated for 2 days by phorbol 12-myristate 13-acetate (PMA) before infection and then cultured in the presence of low-molecular weight B-cell growth factor (LMW-BCGF). Expression of virus envelope glycoprotein (gp) 120 could also be detected on a subpopulation of B cells (CD19+, CD22+) by flow cytometry. Blocking experiments with monoclonal antibodies (MoAbs) against CD4, CD21 (complement receptor 2 [CR2]), CD35 (CR1), CD19, and CD5 surface molecules indicated that infection of B cells involves CD4, CD21, and CD35 antigens. Indeed, blocking of CD4 receptor inhibited 10% of p24 production, and blocking of both CD21 and CD35 led to extinction of p24 signal. CR-dependent pathway is thus a major route for C'-ADE of HIV infection in normal B cells. Our results emphasize the importance of studying interactions between HIV and the complement system for better understanding infection mechanisms and the major dysfunctions of B cells in HIV-infected individuals.

B-Lymphocytes↗

PubMed1995

A decision support tool for antibiotic therapy.

We developed a decision support tool to assist physicians anticipating the need for antibiotic therapy. The initial screen alerts physicians of pertinent patient information, provides direct access to other essential medical information, and stimulates clinical judgment by suggesting an antibiotic regimen. The decision support tool also suggests the dose and interval for any ordered antibiotics selected by the physicians. During a 7-month pilot study, all antibiotics for patients admitted to the Shock/Trauma/Respiratory Intensive Care Unit (STRICU) were ordered using the decision support tool. Clinical data from the study period and a 12-month control period (the previous year) were collected and compared. The decision support tool was used to order antibiotics 588 times during the study period and the suggested antibiotics were used 218 (37%) times. The computer suggested dosages were used over 90% of the time. The mean cost of antibiotics was $87.00 (p < 0.04) less per patient during the study period as compared to the control period. Prospective assessment revealed only 3 antibiotic adverse drug events (ADEs) (0.9%) among 336 study patients as compared to 15 ADEs (2.4%) among 626 control patients (p = 0.164).

Anti-Bacterial Agents↗

PubMed1995

[Role of vestibular and visual analyzers in changes of postural activity of patients with childhood cerebral palsy in the process of treatment with space technology].

The paper presents the findings of stabiligraphic investigations of children afflicted with the hyperkinetic child's cerebral paralysis treated with the method of graduated wearing suit ADELI. This suit is a modification of space-designated PINGUIN used to counteract the adverse effect of long-term microgravity on the skeletal muscles and the skeleton. 30 children were investigated prior to, immediately after, and in a delayed period after this treatment. A group of 11 healthy volunteers were also investigated as their control. The program of investigation included routine stabilimetry, the station test, and head rolling tests. The results demonstrate that in healthy subjects the standing pose is primarily acquired and sustained by means of the visual analyzer, whereas the CCP patients pose could attain this pose with a significantly weakened control by the visual analyzer. Application of ADELI increases the role of visual analyzer in the control of standing pose. Following the treatment, the stabilimetric indices of patients changed for the better and approached those in healthy subjects.

Adolescent↗

PubMed1995

2-Hydroxyadenine (isoguanine) as oxidative DNA damage: its formation and mutation inducibility.

In our experiments we found that hydroxylation occurs at the C-2 position of adenine by oxygen radical treatment (Fe(2+)-EDTA) of dA, dATP, and single- and double-stranded DNA. This oxidatively damaged base, 2-hydroxyadenine (also known as isoguanine), was produced more efficiently in monomers than in polynucleotides. 2-Hydroxydeoxyadenosine triphosphate was incorporated opposite T and C in a DNA template by DNA polymerase alpha and only opposite T by the Klenow fragment. The Klenow fragment, DNA polymerases alpha and beta incorporated dTMP and other nucleotides opposite 2-OH-Ade in DNA templates in vitro in a sequence-dependent manner. These results suggest that the formation of 2-OH-Ade in DNA will induce mutations in cells.

Base Sequence↗

PubMed1996

Neutralizing and infection-enhancing antibody responses do not correlate with the differential pathogenicity of SIVmac239delta3 in adult and infant rhesus monkeys.

Variants of SIV containing a deletion in the nef gene are attenuated in adult macaques, where they provide protection from challenge with pathogenic SIV, but the mechanism of protection remains unknown. One of these attenuated variants carrying deletions in nef, vpr, and NRE (SIVmac239delta3) was recently found to be pathogenic in infant macaques exposed to the virus at birth. We investigated whether inadequate or inappropriate antiviral humoral immune responses could explain why this virus causes disease in infant macaques. Plasma samples from four infants infected with SIVmac251 and five infants and two adults infected with SIVmac239delta3 were evaluated for neutralizing Abs to a laboratory-passaged stock of SIVmac251, an animal challenge stock of SIVmac239/nef-open, and a stock of SIVmac239delta3 to which animals were exposed. Plasma samples were evaluated further for complement-mediated Ab-dependent enhancement (C'-ADE) of SIVmac239/nef-open in vitro. High-titer neutralizing Abs to SIVmac251 were detected in plasma samples from adults and most infants within 3 to 5 wk of infection with either virus. Neutralizing Abs to SIVmac239/nef-open and SIVmac239delta3 developed more slowly, being undetectable before 23 to 63 wk of infection. Timing, magnitude, and breadth of neutralizing Ab responses did not correlate with progression to disease or lack thereof and gave no indication of an impaired humoral immune response in infants. Furthermore, C'-ADE was detected equally in plasma samples from adults and infants. The results indicate that infection with SIVmac239delta3 causes disease in infant macaques despite their mounting of antiviral humoral immune responses comparable to those of adults.

Age Factors↗

PubMed1996

Analysis of spontaneous and double-strand break-induced recombination in rad mutants of S. pombe.

Schizosaccharomyces pombe strains containing direct repeats of adeó heteroalleles separated by a functional uro4+ gene, and a DNA site for induction of a double-strand break (DSB), have been used to analyze pathways of spontaneous and DSB-induced intrachromosomal mitotic recombination. These substrates yield Ade+ Ura+ convertants or Ade+ Ura- deletions, by the DSB/gap repair and single-strand annealing (SSA) pathways of recombination, respectively. In S. cerevisiae, the DSB/gap repair pathway is RAD52 dependent, and the RAD1 and RAD10 genes are involved in the SSA pathway. We have sought to understand the genetic control of the pathways of mitotic recombination in S. pombe by determining the effects of mutations in six rad genes involved in DNA repair: rad1 and rad3 involved in checkpoint control in response to unreplicated or damaged DNA; rad5 (homologue of S. cerevisiae RAD3) and rad10 (homologue of S. cerevisiae RAD1) involved in nucleotide excision repair; rad21 and rad22 (homologue of S. cerevisiae RAD52) involved in the repair of ionizing radiation-induced DNA damage. The results suggest that the genetic control of the pathways of spontaneous and DSB-induced mitotic intrachromosomal recombination in S. pombe is different from that in S. cerevisiae.

Adenosine Triphosphatases↗

PubMed1997

[Genetic control of purine biosynthesis in the yeast Pichia methanolica. "Roman's effect" in red adenine-dependent pur6 and pur7 mutants].

Most ade1 and ade2 mutants of the yeast Pichia methanolica generate white and pink secondary colonies (SCs) on the surface of red colonies in complete medium. The formation of SCs was shown to be caused by "Roman's effect" described in Saccharomyces cerevisiae. This effect is known to result from the preferential growth in a colony of spontaneous mutations for genes controlling the first five steps of purine biosynthesis. It has been found that the ADE3, ADE5, ADE4, 7, and ADE8 loci correspond to these genes. In studies on twelve red adenine-dependent mutants, the expression of Roman's effect was shown to vary in different cultures, dependent on the original mutant ade1 and ade2 alleles. It was assumed that spontaneous mutability of each gene of purine biosynthesis ADE ade does not depend on mutations in other genes of this biosynthetic pathway. On the basis of this assumption and data from genetic analysis of mutants, it is concluded that the ade1 and ade2 mutant alleles do not determine the mutability level but affect the level of selective advantage of double mutants. This conclusion was used to estimate the lowest frequencies of spontaneous mutability of early purine genes in P. methanolica (with respect to the identified mutants). As calculated for one red mutant, frequencies of spontaneous mutations in the most mutable ADE5 gene and in the least mutable ADE8 gene of this group were 2.5 x x 10(-8) and 0.4 x 10(-8), respectively.

Adenine↗

PubMed1998

The alcohol deprivation effect in the alcohol-preferring P rat under free-drinking and operant access conditions.

The alcohol-deprivation effect (ADE) was examined under 4-hr operant and 24-hr free-choice alcohol access in the alcohol-preferring (P) rat after deprivation intervals from 2 to 4 weeks. Results indicated that adult male P rats responding for 6 weeks on a concurrent FR-5/FR-1 schedule of reinforcement for alcohol and water, respectively, and then deprived of alcohol for 2 weeks, demonstrated a 40% increase in alcohol responding during the first 60 min of alcohol reinstatement. The alcohol deprivation effect was temporary, however, as responding did not differ from baseline levels on the second day of reinstatement. In a second experiment, weanling male and female P rats received 7 weeks of continuous access to alcohol, beginning at 21 days of age, and were then deprived of alcohol for 4 weeks. On the first day of alcohol reinstatement, P rats exhibited a 40% to 45% increase from baseline alcohol drinking levels, with alcohol intake returning to baseline levels by the 3rd day of reinstatement. Although alcohol intake was higher in females than in males when adjustment was made for body weight, there were no gender differences in the magnitude of the alcohol deprivation effect. Taken together, these results indicate that the ADE is a long-lasting phenomenon that occurs under both operant and continuous access conditions in the P rat, and thus these rats may be useful models for the study of factors involved in relapse of alcohol drinking.

Alcohol Drinking↗

PubMed1998

Role of potassium channels in halothane-epinephrine arrhythmias.

It has been reported that antiarrhythmic drugs possessing the property of potassium channel blockade were most effective in preventing halothane-epinephrine induced arrhythmias. Recent attention has focused on ATP-sensitive potassium (K(ATP)) channels because of their contribution to the cardiovascular actions of volatile anesthetics. The present study was designed to evaluate whether K(ATP) channels or transient outward potassium channels (Ito) were involved in the mechanism of halothane-epinephrine arrhythmias in rat. Rats were anesthetized with halothane (1.5%), and the lungs were mechanically ventilated. The arrhythmogenic thresholds of epinephrine during halothane anesthesia were determined in 74 rats receiving saline or one of tested agents. The arrhythmogenic dose of epinephrine (ADE) was significantly increased by a K(ATP) channel opener, JTV506 (P < 0.01), and had a tendency to be increased by other K(ATP) channel openers, cromakalim, nicorandil, KRN2391 and Y 26763, but were not affected by a K(ATP) channel blocker, glibenclamide. The Ito blocker, 4-aminopyridine, also significantly increased the ADE. Epinephrine produced second-degree or complete atrioventricular block in 4 out of 7 rats receiving glibenclamide. These results suggest that Ito but not K(ATP) channels might be involved in the mechanism in producing halothane-epinephrine arrhythmias.

Adenosine Triphosphate↗

PubMed1995

Intracellular degradation of apolipoprotein B generates an N-terminal 70 kDa fragment in the endoplasmic reticulum.

Regulated apoB degradation in HepG2 cells occurs in the endoplasmic reticulum (ER), is catalyzed by an N-acetylleucylleucylnorleucinal (ALLN)-sensitive proteinase, and generates a specific 70 kDa fragment (Adeli, K., 1994, J. Biol. Chem. 269, 9166-9175) [corrected]. In the present report, we have characterized the 70 kDa fragment by immunoprecipitation of permeabilized HepG2 cells with a battery of monoclonal antibodies against various sites on the apoB molecule. N-Terminal monoclonal antibodies (1D1 and 2D8) were capable of binding to the 70 kDa fragment suggesting that this polypeptide is an N-terminal fragment of the intact apoB. Subcellular fractionation of permeabilized cells and carbonate extraction resulted in the detection of the 70 kDa fragment in the ER lumen. Endoglycosidase H treatment confirmed that the fragment is N-linked glycosylated. We hypothesize that the ALLN-sensitive proteinase which may be located on the luminal side of the ER membrane, catalyzes an initial cleavage of apoB near the N-terminus generating a 70 kDa fragment, which is then released into the ER lumen.

Animals↗

PubMed1982

Isolation of the mature subunit of delta-aminolaevulinate synthase from embryonic chick liver.

We presented evidence indicating that the established procedure for purifying delta-aminolaevulinate (ALA) synthase from embryonic-chick liver yielded an enzyme with a partially degraded subunit of molecular weight 51000 [Ades & Harpe (1981) J. Biol. Chem. 256, 9329-9333]. We now report the purification from livers of porphyric embryos of a preparation of ALA synthase which consisted primarily of a 63000-Da polypeptide and a component migrating as a smear of polypeptides with a minimum molecular weight of 52 000. Neither component could be recovered from liver mitochondria of normal embryos, where the amounts of ALA synthase were relatively low. The 52 000-Da component had been established to be the partially degraded subunit of the enzyme. Peptide-mapping analyses indicated that the 63 000- and the 52 000-Da components possessed significant structural homologies, and it was concluded that the 63 000-Da polypeptide represented the mature subunit of ALA synthase.

5-Aminolevulinate Synthetase↗

PubMed1983

Biogenesis of mitochondrial proteins. Regulation of production of delta-aminolaevulinate synthase by haemin in embryonic-chick liver.

The effect of haemin on the biogenesis of delta-aminolaevulinate synthase (ALA synthase) was investigated in primary cultures of embryonic-chick liver. The activity of the enzyme and the amount of the enzyme detected by 'immune-blotting' were determined in hepatocytes incubated with the porphyrogenic agent allylisopropylacetamide. The results of these studies indicated that the loss in ALA synthase activity in cells incubated in the presence of haemin (10 microM) was roughly proportional to a loss in the immune-reactive mass of the enzyme. Haemin was as effective as cycloheximide in causing depletion of ALA synthase in hepatocytes. We had previously established that haemin blocked the maturation of the precursor of ALA synthase [Ades (1983) Biochem. Biophys. Res. Commun. 110, 42-47]. From results reported in the present paper on analyses of immune-precipitated ALA synthase after pulse-labelling with [35S]methionine in the presence and in the absence of haemin, we determined that the inhibition of processing of pre-ALA synthase in cells by haemin was concentration-dependent. A concentration of 2 microM in the culture medium blocked the processing of pre-ALA synthase by 50% in hepatocytes. We also determined that, after inhibition of its maturation by haemin, pre-ALA synthase turned-over with a half-time of 30 min; on the other hand, mature ALA synthase turned-over with a half-time of 120 min.

5-Aminolevulinate Synthetase↗

PubMed1995

Human microvascular endothelial tissue culture cell model for studying pathogenesis of Brazilian purpuric fever.

Brazilian purpuric fever (BPF) is a fulminant pediatric disease characterized by fever, with rapid progression to purpura, hypotensive shock, and death. All known BPF cases have been caused by three clones of Haemophilus influenzae biogroup aegyptius and have occurred in either Brazil or Australia. Using an immortalized line of human vascular endothelial cells, we developed an in vitro assay that identifies all known BPF-causing H. influenzae biogroup aegyptius strains (R. S. Weyant, F. D. Quinn, E. A. Utt, M. Worley, V. G. George, F. J. Candal, and E. W. Ades, J. Infect. Dis. 169:430-433, 1994). With multiplicities of infection (MOIs) as low as one bacterium per 1,000 tissue culture cells, BPF-associated strains produce a unique cytotoxic effect in which the tissue culture cells detach and aggregate in large floating masses after 48 h of incubation. In this study, using a BPF-associated strain and a non-BPF-associated control, we demonstrated that strains which produce the cytotoxic phenotype were able to replicate intracellularly whereas non-BPF-associated strains, with MOIs of > or = 1,000 did not replicate and did not produce the phenotype. We also showed that this phenotype is not caused by the activity of an endotoxin or the release of some other compound from the bacterial cell, since neither gamma irradiation-killed whole BPF clone bacteria nor bacterial cell fractions at MOIs of > 1,000 produced the cytotoxic effect. Furthermore, bacteria in numbers equal to MOIs of > 1,000 treated with chloramphenicol did not produce the cytotoxic phenotype, suggesting a requirement for bacterial protein synthesis. In addition, viable bacteria separated from the tissue culture monolayer by a 0.2-micron-pore-size membrane also failed to produce the phenotype. The ability of the bacterium to invade, replicate, and produce the phenotype appears to be primarily parasite directed since phagocytosis, pinocytosis, and eukaryotic protein synthesis inhibitors, including cycloheximide, cytochalasin D, and methylamine, had no effect on the ability of the bacterium to invade and cause a cytotoxic response. Understanding the basic mechanisms involved in this tissue-destructive process should enhance our knowledge of the general pathogenesis of BPF.

Bacterial Adhesion↗

PubMed1980

The transport of proteins into yeast mitochondria. Kinetics and pools.

By double isotope pulse-labeling of yeast cells, we determined the kinetics of labeling at 9 degrees C of total mitochondrial membrane, mitochondrial matrix, and cytosolic proteins, the alpha, beta, and gamma subunits of F1 ATPase, and glyceraldehyde-3-phosphate dehydrogenase. We find that none of the mitochondrial proteins show a lag in the incorporation of label compared to cytosolic proteins. These results argue against the existence in the cytosol of large pools of mitochondrial proteins awaiting transport into the organelle. Cycloheximide addition during the pulse stops [35S]methionine incorporation into mitochondrial membrane and cytosolic proteins rapidly (approximately 1 min) and with identical kinetics. Compared to cytosolic protein, however, there is a persistent incorporation of label into mitochondria after a chase with cold methionine (t1/2 approximately 1.5 min at 9 degrees C) which cannot be accounted for solely by chain completion. We conclude that this continued incorporation reflects some transport process in addition to a completion of a round of translation. When cells are labeled during a synchronous "restart" of protein synthesis, where ribosome run-off from mRNA was first induced either by incubating cells for 4 h at 0 degrees C or by treatment with 5 mM aurintricarboxylic acid, the initial rate of incorporation of label into mitochondrial protein now lags behind that of cytosolic proteins. From these results and those in the accompanying report (Ades, I.Z., and Butow, R.A. (1980) J. Biol. Chem. 255, 9918-9924) we propose that the translation of mRNA specific for mitochondrial proteins takes place in the cytoplasm and that at least a portion of the polysomes are then transported and bind to the outer mitochondrial membrane, followed by completion of translation and transfer of the newly synthesized polypeptides into the mitochondria. From a consideration of all of the available data on protein transport into mitochondria in yeast, we conclude that cytoplasmic polysomes bound to the outer mitochondrial membrane function in the transport of proteins into mitochondria by a process not necessarily mutually exclusive of post-translational transport.

Adenosine Triphosphatases↗

PubMed1999

An immunomodulatory polysaccharide-rich substance from the fruit juice of Morinda citrifolia (noni) with antitumour activity.

The fruit juice of Morinda citrifolia (noni) contains a polysaccharide-rich substance (noni-ppt) with antitumour activity in the Lewis lung (LLC) peritoneal carcinomatosis model. Therapeutic administration of noni-ppt significantly enhanced the duration of survival of inbred syngeneic LLC tumour bearing mice. It did not exert significant cytotoxic effects in an adapted culture of LLC cells, LLC1, but could activate peritoneal exudate cells (PEC) to impart profound toxicity when co-cultured with the tumour cells. This suggested the possibility that noni-ppt may suppress tumour growth through activation of the host immune system. Concomitant treatment with the immunosuppressive agent, 2-chloroadenosine (C1-Ade) or cyclosporin (cys-A) diminished its activity, thereby substantiating an immunomodulatory mechanism. Noni-ppt was also capable of stimulating the release of several mediators from murine effector cells, including tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-10, IL-12 p70, interferon-gamma (IFN-gamma) and nitric oxide (NO), but had no effect on IL-2 and suppressed IL-4 release. Improved survival time and curative effects occurred when noni-ppt was combined with sub-optimal doses of the standard chemotherapeutic agents, adriamycin (Adria), cisplatin (CDDP), 5-fluorouracil (5-FU), and vincristine (VCR), suggesting important clinical applications of noni-ppt as a supplemental agent in cancer treatment.

Adjuvants, Immunologic↗