Search PubMed⌕ Search

Biomedical subjects

T C Chou

Publications and source records attributed to T C Chou.

At least 55 records · Page 3Linked to original sources
PubMed1999

Multimodal cancer treatment mediated by a replicating oncolytic virus that delivers the oxazaphosphorine/rat cytochrome P450 2B1 and ganciclovir/herpes simplex virus thymidine kinase gene therapies.

Multimodal therapy is generally more effective than single-agent treatment for cancer. rRp450 is an engineered herpes simplex viral mutant that replicates in and kills tumor cells in a relatively selective fashion. It also expresses, in infected cells, the cyclophosphamide (CPA)-sensitive rat cytochrome P450 2B1 (CYP2B1) and the ganciclovir (GCV)-sensitive herpes simplex virus thymidine kinase (HSV-TK) transgenes. We show that cultured rat 9L and human U87deltaEGFR glioma cells, infected and lysed by rRp450, also exhibit supra-additive sensitivity to both CPA and GCV, as determined by Chou-Talalay synergy analysis. DNA cross-linking, assayed by ethidium bromide fluorescence, was significantly inhibited in the presence of GCV, suggesting that interactions between the CPA/CYP2B1 and GCV/HSV-TK gene therapies occurred at the level of DNA repair. In vivo, regression of 9L s.c. tumor volumes in athymic mice was achieved only by the multimodal treatment allowed by rRp450 viral oncolysis combined with CPA/CYP2B1 and GCV/HSV-TK gene therapies, whereas all other treatment combinations produced only tumor growth retardation.

Animals↗
PubMed1999

Selective, covalent modification of beta-tubulin residue Cys-239 by T138067, an antitumor agent with in vivo efficacy against multidrug-resistant tumors.

Microtubules are linear polymers of alpha- and beta-tubulin heterodimers and are the major constituents of mitotic spindles, which are essential for the separation of chromosomes during mitosis. Here we describe a synthetic compound, 2-fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene (T138067), which covalently and selectively modifies the beta1, beta2, and beta4 isotypes of beta-tubulin at a conserved cysteine residue, thereby disrupting microtubule polymerization. Cells exposed to T138067 become altered in shape, indicating a collapse of the cytoskeleton, and show an increase in chromosomal ploidy. Subsequently, these cells undergo apoptosis. Furthermore, T138067 exhibits cytotoxicity against tumor cell lines that exhibit substantial resistance to vinblastine, paclitaxel, doxorubicin, and actinomycin D. T138067 is also equally efficacious in inhibiting the growth of sensitive and multidrug-resistant human tumor xenografts in athymic nude mice. These observations suggest that T138067 may be clinically useful for the treatment of multidrug-resistant tumors.

Animals↗
PubMed1999

Design of antineoplastic agents based on the "2-phenylnaphthalene-type" structural pattern. 4. Synthesis and biological activity of 2-chloro-3-(substituted phenoxy)-1, 4-naphthoquinones and related 5,8-dihydroxy-1,4-naphthoquinones.

The intermediate in the preparation of 1,3,7, 10-tetrahydroxybenzo[b]naphtho[2,3-d]furan-6,11-dione (2), 2-chloro-5,8-dimethoxy-3-(3,5-dimethoxyphenoxy)-1,4-naphthoquinone (8h), and corresponding hydroxyl, methoxyl, and acetoxyl analogues was found to possess interesting inhibitory activities in a number of cytotoxic test systems. Activities were also noticed in some 5, 8-dihydroxy-1,4-naphthoquinone derivatives. A structure-activity discussion of compounds of this series is presented. The newly uncovered biological activity of 2-chloro-3-(substituted phenoxyl)-1, 4-naphthoquinones and 2,3-bis(substituted phenoxy)-1, 4-naphthoquinones may suggest an approach for the development of new classes of antineoplastic agents.

Antineoplastic Agents↗
PubMed1999

Phase I study of the sequential administration of edatrexate and paclitaxel in patients with advanced solid tumors.

BACKGROUND: The antifolate edatrexate and the microtubule-stabilizing agent paclitaxel have both demonstrated single-agent activity in lung and breast cancer. In vitro, the sequential combination of edatrexate followed by paclitaxel produced synergistic antitumor effects. This trial was designed to find the maximum tolerated doses of edatrexate and paclitaxel when given every two weeks utilizing this sequential schedule. PATIENTS AND METHODS: Thirty-four patients with solid tumors received edatrexate intravenously on days 1 and 15 and paclitaxel intravenously as a three-hour infusion on days 2 and 16 of each 28-day cycle. Edatrexate was escalated from 40 to 120 mg/m2 and the paclitaxel dose fixed at 135 mg/m2. When the maximum-tolerated dose was not reached, edatrexate was fixed at 120 mg/m2 and paclitaxel escalated to 175 and 210 mg/m2. RESULTS: All 34 patients were assessable. The maximum tolerated doses were 120 mg/m2 of edatrexate and 210 mg/m2 of paclitaxel. Grade 3 myalgia, peripheral neuropathy, leukopenia, and an infusion-related reaction occurred. Eight patients with non-small-cell lung cancer and one with bladder cancer achieved major objective responses. CONCLUSIONS: The recommended phase II doses are 120 mg/m2 of edatrexate days 1 and 15 and 175 mg/m2 of paclitaxel as a three-hour infusion days 2 and 16 of a 28 day cycle. These results warrant phase II trials of the combination leading to phase III studies comparing the two drugs to a single agent to confirm the preclinical evidence of synergy.

Adult↗
PubMed1999

Stimulation of TNF-alpha, IL-1beta and nitrite release from mouse cultured spleen cells and lavaged peritoneal cells by mastoparan M.

Chemically synthesized mastoparan M, a tetradecapeptide toxin of venom (INLKAIAALAKKLL), was used in the experiments described. After addition of mastoparan M to cultures of mouse macrophages in vitro, tumour necrosis factor-alpha (TNF-alpha) and interleukin 1beta (IL-1beta) were detected in the culture fluids by 12 h and their highest accumulation was observed by 24 h. Mastoparan M induced increases in both TNF-alpha secretion and mRNA level at the same time. Nitrite levels, which reflect nitric oxide synthesis, were also found to increase in the macrophage cultures at 24 h after mastoparan M addition. In vivo studies showed that mastoparan M induced the formation and accumulation of TNF-alpha, IL-1beta and nitrite in the peritoneal exudates of mice much faster at 90 min, 120 min and 180 min after mastoparan M injection, respectively. Similarly, significant increases in myeloperoxidase activity, a marker for neutrophil and macrophage content, were observed in the peritoneal lavage cells after intraperitoneal injection of mastoparan M. However, induction of nitrite by mastoparan M was completely inhibited by simultaneous addition of antimouse TNF-alpha antibody to the macrophage cultures. These results suggest that modulation of both neutrophil and macrophage influx by mastoparan M may be conveyed through TNF-alpha and IL-1beta secretion accompanied by nitrite formation.

Animals↗
PubMed1998

Desoxyepothilone B is curative against human tumor xenografts that are refractory to paclitaxel.

The epothilones are naturally occurring, cytotoxic macrolides that function through a paclitaxel (Taxol)-like mechanism. Although structurally dissimilar, both classes of molecules lead to the arrest of cell division and eventual cell death by stabilizing cellular microtubule assemblies. The epothilones differ in their ability to retain activity against multidrug-resistant (MDR) cell lines and tumors where paclitaxel fails. In the current account, we focus on the relationship between epothilone and paclitaxel in the context of tumors with multiple drug resistance. The epothilone analogue Z-12,13-desoxyepothilone B (dEpoB) is >35,000-fold more potent than paclitaxel in inhibiting cell growth in the MDR DC-3F/ADX cell line. Various formulations, routes, and schedules of i.v. administration of dEpoB have been tested in nude mice. Slow infusion with a Cremophor-ethanol vehicle proved to be the most beneficial in increasing efficacy and decreasing toxicity. Although dEpoB performed similarly to paclitaxel in sensitive tumors xenografts (MX-1 human mammary and HT-29 colon tumor), its effects were clearly superior against MDR tumors. When dEpoB was administered to nude mice bearing our MDR human lymphoblastic T cell leukemia (CCRF-CEM/paclitaxel), dEpoB demonstrated a full curative effect. For human mammary adenocarcinoma MCF-7/Adr cells refractory to paclitaxel, dEpoB reduced the established tumors, markedly suppressed tumor growth, and surpassed other commonly used chemotherapy drugs such as adriamycin, vinblastine, and etoposide in beneficial effects.

Animals↗
PubMed1998

Desoxyepothilone B: an efficacious microtubule-targeted antitumor agent with a promising in vivo profile relative to epothilone B.

A new class of 16-membered macrolides, the epothilones (Epos), has been synthesized and evaluated for antitumor potential in vitro and in vivo. Recent studies in these and other laboratories showed that epothilones and paclitaxel (paclitaxel) share similar mechanisms of action in stabilizing microtubule arrays as indicated by binding-displacement studies, substitution for paclitaxel in paclitaxel-dependent cell growth, and electron microscopic examinations. The present study examined cell growth-inhibitory effects in two rodent and three human tumor cell lines and their drug-resistant sublines. Although paclitaxel showed as much as 1, 970-fold cross-resistance to the sublines resistant to paclitaxel, adriamycin, vinblastine, or actinomycin D, most epothilones exhibit little or no cross-resistance. In multidrug-resistant CCRF-CEM/VBL100 cells, IC50 values for EpoA (1), EpoB (2), desoxyEpoA (3) (dEpoA), desoxyEpoB (4) (dEpoB), and paclitaxel were 0.02, 0.002, 0.012, 0.017, and 4.14 microM, respectively. In vivo studies, using i.p. administration, indicated that the parent, EpoB, was highly toxic to mice and showed little therapeutic effect when compared with a lead compound, dEpoB. More significantly, dEpoB (25-40 mg/kg, Q2Dx5, i.p.) showed far superior therapeutic effects and lower toxicity than paclitaxel, doxorubicin, camptothecin, or vinblastine (at maximal tolerated doses) in parallel experiments. For mammary adenocarcinoma xenografts resistant to adriamycin, MCF-7/Adr, superior therapeutic effects were obtained with dEpoB compared with paclitaxel when i.p. regimens were used. For ovarian adenocarcinoma xenografts, SK-OV-3, dEpoB (i.p.), and paclitaxel (i. v.) gave similar therapeutic effects. In nude mice bearing a human mammary carcinoma xenograft (MX-1), marked tumor regression and cures were obtained with dEpoB.

Animals↗
PubMed1998

Reversal of anticancer multidrug resistance by the ardeemins.

Two "reverse prenyl" hexahydropyrroloindole alkaloids, 5-N-acetylardeemin and 5-N-acetyl-8-demethylardeemin, were evaluated as reversal agents in cells exhibiting a multidrug resistant (MDR) phenotype. These ardeemins (i) reversed drug resistance to vinblastine (VBL) or to taxol as much as 700-fold at relatively noncytotoxic concentrations in vitro; (ii) as a single agent at high concentrations killed MDR cells more efficaciously than the respective parent wild-type cells; and (iii) exhibited strong synergistic effects with doxorubicin (DX) and VBL against the growth of MDR neoplastic cells, and to a lesser extent, of the parent wild-type cells. Mechanistic studies showed that photoaffinity labeling of P-glycoprotein (Pgp) with [3H] azidopine was competitively inhibited by the ardeemins. Resistance to DX in MDR-[Pgp+ and MDR-associated protein (MRP)+], MDR-Pgp+, lung resistance protein (LRP)+-expressing, and wild-type lung cancer cells were reversed 110- to 200-fold, 50- to 66-fold, 7- to 15-fold, and 0.9- to 3-fold, respectively, by 20 microM of the ardeemins. Moreover, these compounds increased the intracellular accumulation of VBL and markedly decreased its efflux. Finally, in vivo combination studies demonstrated that nontoxic doses of the ardeemins with DX significantly improved the chemotherapeutic effects in B6D2F1 mice bearing DX-resistant P388 leukemia, and nude mice bearing human MX-1 mammary carcinoma xenografts. The above features indicate that the ardeemins may have utility in the therapy of cancer.

Alkaloids↗
PubMed1998

Synergistic anticancer effects of ganciclovir/thymidine kinase and 5-fluorocytosine/cytosine deaminase gene therapies.

BACKGROUND: A bacterial enzyme, Escherichia coli cytosine deaminase, which converts the prodrug 5-fluorocytosine into the toxic drug 5-fluorouracil, and a viral enzyme, herpes simplex virus thymidine kinase, which converts ganciclovir from an inactive prodrug to a cytotoxic agent by phosphorylation, are being actively investigated for use in gene therapy for cancer. The purpose of this study was to determine whether combining these prodrug-activating gene therapies might result in enhanced anticancer effects. METHODS: Rat 9L gliosarcoma cells were transfected with plasmids containing the E. coli cytosine deaminase gene (9L/CD cells), with plasmids containing the herpes simplex virus thymidine kinase gene (9L/TK cells), or with both expression plasmids (9L/CD-TK cells). The drug sensitivities of the cell lines were evaluated; in addition, the sensitivities of 9L and 9L/CD-TK cells mixed in varied proportions were measured. The effects of prodrug treatment on 9L/CD-TK tumor growth (i.e., size and volume) in nude mice were monitored. The isobologram method of Loewe and the multiple drug-effect analysis method of Chou-Talalay were used to measure the interaction between the two prodrug-activating gene therapies. To elucidate the mechanism of interaction, the phosphorylation of ganciclovir in 9L/CD-TK cells after varying prodrug treatments was studied. RESULTS AND CONCLUSIONS: The presence of transfected cytosine deaminase and thymidine kinase genes in 9L gliosarcoma cells reduced cell survival, both in vitro and in vivo, following treatment with the relevant prodrugs; the effects of the two components appeared to be synergistic and related mechanistically to the enhancement of ganciclovir phosphorylation by thymidine kinase following 5-fluorouracil treatment.

Animals↗
PubMed1998

Dantrolene inhibits nitric oxide synthase in rat alveolar macrophages treated with lipopolysaccharide and interferon-gamma.

PURPOSE: To examine the effects of dantrolene on nitric oxide (NO) production and on the activity and protein expression of inducible nitric oxide synthase (iNOS) induced by lipopolysaccharide (LPS) plus interferon-gamma (IFN gamma) in rat alveolar macrophages. METHODS: Pulmonary alveolar macrophages isolated from Sprague-Dawley rats were used. After incubation of macrophages with dantrolene (1 to 100 microM) and LPS (1 microgram.ml-1) and IFN-gamma (100 u.ml-1) for 24 hr, the cell-free medium was removed for measuring the nitrite and tumour necrosis factor-alpha (TNF-alpha) levels by Griess reaction and ELISA kit, respectively. The harvested macrophages were also used to determine the activity of iNOS by using the conversion of [3H]-L-arginine to [3H]-L-citrulline method. Protein expression of iNOS was detected by Western blot analysis. RESULTS: In rats alveolar macrophages, (i) dantrolene (1 to 100 microM) caused a dose-dependent suppression of the production of nitrite and TNF-alpha induced by LPS (1 microgram.ml-1) plus IFN-gamma (100 u.ml-1) and (ii) dantrolene (100 microM) inhibited the activity (by 37 +/- 5%, P < 0.01) and protein expression (by 39 +/- 12%, P < 0.01) of iNOS in response to LPS plus IFN-gamma. CONCLUSION: Dantrolene inhibits NO production as well as the activity and expression of iNOS in alveolar macrophages treated with LPS plus IFN-gamma, which may be associated with the reduction of TNF-alpha production.

Animals↗
PubMed1998

Quantitation of chemopreventive synergism between (-)-epigallocatechin-3-gallate and curcumin in normal, premalignant and malignant human oral epithelial cells.

An in vitro model for oral cancer was used to examine the growth inhibitory effects of chemopreventive agents when used singly and in combination. The model consists of primary cultures of normal oral epithelial cells, newly established cell lines derived from dysplastic leukoplakia and squamous cell carcinoma. Two naturally occurring substances, (-)-epigallocatechin-3-gallate (EGCG) from green tea and curcumin from the spice turmeric were tested. Cells were treated singly and in combination and effects on growth determined in 5-day growth assays and by cell cycle analysis. Effective dose 50s and the combination index were calculated with the computerized Chou-Talalay method which is based on the median-effect principle. Agents were shown to differ in their inhibitory potency. EGCG was less effective with cell progression; the cancer cells were more resistant than normal or dysplastic cells. In contrast, curcumin was equally effective regardless of the cell type tested. Cell cycle analysis indicated that EGCG blocked cells in G1, whereas curcumin blocked cells in S/G2M. The combination of both agents showed synergistic interactions in growth inhibition and increased sigmoidicity (steepness) of the dose-effect curves, a response that was dose and cell type dependent. Combinations allowed for a dose reduction of 4.4-8.5-fold for EGCG and 2.2-2.8-fold for curcumin at ED50s as indicated by the dose reduction index (DRI). Even greater DRI values were observed above ED50 levels. Our results demonstrate that this model which includes normal, premalignant and malignant oral cells can be used to analyse the relative potential of various chemopreventive agents. Two such naturally-occurring agents, EGCG and curcumin, were noted to inhibit growth by different mechanisms, a factor which may account for their demonstrable interactive synergistic effect.

Anticarcinogenic Agents↗
PubMed1998

The inhibition by dantrolene of L-arginine transport and nitric oxide synthase in rat alveolar macrophages.

UNLABELLED: Dantrolene decreases the free cytosolic Ca2+ level via inhibition of calcium release from the sacroplasmic reticulum. However, the effect of dantrolene on L-arginine transport and nitric oxide synthase (NOS) activity is still unknown. In this study, we examined the effects of dantrolene on L-arginine transport and activity of inducible nitric oxide synthase (iNOS) induced by lipopolysaccharide (LPS) and interferon gamma (IFN-gamma) in rat alveolar macrophages. Incubation of cells with LPS (1 microg/mL) and IFN-gamma (100 u/mL) for 24 h resulted in significant increases in nitrite production and L-arginine transport. In the presence of dantrolene (100 microM) or inhibitors of NOS, such as aminoguanidine (100 microM), N(G)-monomethyl-L-arginine (100 microM), the nitrite production and L-arginine transport were significantly inhibited compared with that in the LPS + IFN-gamma group. Furthermore, the results of kinetic analysis indicate that the suppression of L-arginine transport by dantrolene was caused by selective decrease of the velocity of transport (Vmax) without affecting the affinity (Km) for L-arginine. In addition, dantrolene also attenuated the activity of iNOS in a dose-dependent manner. We conclude that the mechanisms by which dantrolene attenuated NO synthesis may be associated with the inhibition of availability of L-arginine by reducing the affinity for L-arginine, accompanied by a parallel decrease of the activity of iNOS. IMPLICATIONS: In this study, we demonstrated that dantrolene, a drug that reduces the intracellular Ca2+ level, can inhibit L-arginine availability and inducible nitric oxide synthase activity in macrophages. Our finding may provide a novel therapeutic approach using dantrolene to prevent hypotension associated with an activation of inducible nitric oxide synthase in endotoxemia.

Animals↗
PubMed1998

Synergistic neutralization of simian-human immunodeficiency virus SHIV-vpu+ by triple and quadruple combinations of human monoclonal antibodies and high-titer anti-human immunodeficiency virus type 1 immunoglobulins.

We have tested triple and quadruple combinations of human monoclonal antibodies (MAbs), which are directed against various epitopes on human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins, and a high-titer anti-HIV-1 human immunoglobulin (HIVIG) preparation for their abilities to neutralize a chimeric simian-human immunodeficiency virus (SHIV-vpu+). This virus encodes the HIV-1 strain IIIB env, tat, rev, and vpu genes. The quantitative nature of the Chou-Talalay method (Adv. Enzyme Regul. 22:27-55, 1984) allows ranking of various combinations under identical experimental conditions. Of all triple combinations tested, the most potent neutralization was seen with MAbs 694/98D plus 2F5 plus 2G12 (directed against domains on V3, gp41, and gp120, respectively) as measured by the total MAb concentration required to reach 90% neutralization (90% effective concentration [EC90], 2.0 microg/ml). All triple combinations involving MAbs and/or HIVIG that were tested yielded synergy with combination index values of < 1; the dose reduction indices (DRIs) ranged from 3.1 to 26.2 at 90% neutralization. When four MAbs (the previous three plus MAb F105, directed against the CD4 binding site) were combined, higher neutralization potency (EC90 1.8 microg/ml) and a higher degree of synergy compared to any triple combination were seen. The mean DRIs of the quadruple combination were approximately twice that of the most synergistic triple combination. We conclude that human MAbs targeting different HIV-1 envelope glycoprotein epitopes exhibit strong synergy when used in combination, a fact that could be exploited clinically for passive immunoprophylaxis against HIV-1.

Animals↗
PubMed1998

Experimental focal segmental glomerulosclerosis in mice.

Although a lot of animal models of proteinuria have been established, proposals for the mechanisms of proteinuria are still controversial. In this work, during an 18-day trial, mice injected with a single dose of adriamycin (AD) rapidly showed combined glomerular albuminuria and immunoglobulinuria, progressively elevated levels of nitrite/nitrate in urine, hypercholesterolemia, abnormal renal function, segmentally or globally glomerular hyalinosis/sclerosis associated with tubular atrophy, enhanced glomerular deposition of immunoglobulins and fibrinogen, augmented expression of matrix components in the whole glomerular tuft, and loss of glomerular negative charge property. These laboratory and pathological features are comparatively similar to those of human focal segmental glomerulosclerosis in the advanced state. Juxtamedullary glomeruli appear to be more susceptible to the AD-related nephrotoxicity than those in the superficial renal cortex. A change in size-dependent glomerular permselectivity may precede a charge-dependent defect in glomeruli in this mouse model of proteinuria. Data in this study confirm the hypothesis of glomerular hyperfiltration involved in the pathogenesis of this chronic glomerulopathy associated with proteinuria in mice. In addition, nitric oxide may play a crucial role in the progression of the chronic glomerulopathy model.

Animals↗
PubMed1998

Alterations of nitric oxide synthase expression with aging and hypertension in rats.

The activity and protein expression of endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) were investigated during the development of hypertension in spontaneously hypertensive rats (SHR). SHR and Wistar-Kyoto rats (WKY) were studied at three different ages: 4, 14 to 17, and 63 weeks of age. After treatment with saline or lipopolysaccharide (LPS, 10 mg/kg IV) for 3 hours, the aortas were removed for measurement of NOS activity and protein expression assay by [3H]-L-citrulline formation method and Western blot analysis, respectively. Plasma levels of nitrite/nitrate (NO2-/NO3-) and tumor necrosis factor-alpha (TNF-alpha) were also determined. At 14 to 17 weeks and 63 weeks, the basal activity and protein expression of eNOS in the aortas were significantly lower in SHR than in WKY. In addition, the aged WKY exhibited lower eNOS activity than that of adult WKY, but this change was not seen in SHR. By comparison, the basal activity and protein expression of iNOS were only observed in SHR of the 14-to-17-week group and in the 63-week group; SHR still exhibited higher activities, and these differences were further exaggerated by treatment with LPS. The basal and LPS-induced NO2-/NO3- and TNF-alpha levels in the plasma were also higher in the SHR except the 4-week group. After treatment with quinapril, the basal and LPS-induced expressions of iNOS in SHR were significantly attenuated. Our results demonstrated that alterations of activity and protein expression of eNOS and iNOS occurred in SHR. In addition, aging may reduce the activity of eNOS in WKY but not in SHR. The decline of eNOS activity and/or expression may contribute to the development of hypertension, whereas the increase of iNOS expression may be a consequence of the pathological state of vessels associated with hypertension in SHR. However, the augmented expression of iNOS in SHR was attenuated by antihypertensive therapy, suggesting that the abnormal expression of iNOS is associated with hypertension.

Aging↗
PubMed1998

Pretreatment of colon carcinoma cells with Tomudex enhances 5-fluorouracil cytotoxicity.

The cytotoxic effect of sequence and dose of Tomudex (TX) and 5-fluorouracil (FUra) on an HCT-8 colon carcinoma cell line using a clonogenic assay was evaluated. Synergistic cell kill was obtained with 24 h of exposure to TX followed by 4 h of exposure to FUra. Marginal synergy was obtained with the same sequence but with a 5-day exposure to FUra. The reverse sequence, FUra (either 4 h or 5 days), followed by TX (24 h), resulted in less-than-additive cell kill. The synergistic effect was not due to augmented inhibition of thymidylate synthase, as determined by the measurement of thymidylate synthase activity by tritium release from [5-3H]2'-deoxyuridine. Surprisingly, an increase in intracellular levels of phosphoribosylpyrophosphate was observed after 24 h of exposure to TX, suggesting the possibility of an indirect effect of TX and/or its polyglutamates on purine biosynthesis. Moreover, we observed an increased formation of FUra nucleotides in the cells preexposed to TX, likely due to the increased intracellular levels of phosphoribosylpyrophosphate, that as a consequence led to an enhanced incorporation of FUra into RNA and increased cell killing.

Adenocarcinoma↗
PubMed1997

Synergistic neutralization of a chimeric SIV/HIV type 1 virus with combinations of human anti-HIV type 1 envelope monoclonal antibodies or hyperimmune globulins.

A panel of 14 human IgG monoclonal antibodies (MAbs) specific for envelope antigens of the human immunodeficiency virus type 1 (HIV-1), 2 high-titer human anti-HIV-1 immunoglobulin (HIVIG) preparations, and 15 combinations of MAbs or MAb/HIVIG were tested for their ability to neutralize infection of cultured human T cells (MT-2) with a chimeric simian immunodeficiency virus (SHIV-vpu+), which expressed HIV-1 IIIB envelope antigens. Eleven MAbs and both HIVIGs were neutralizing. When used alone, the anti-CD4-binding site MAb b12, the anti-gp41 MAb 2F5, and the anti-gp120 MAb 2G12 were the most potent. When combination regimens involving two MAbs targeting different epitopes were tested, synergy was seen in all paired MAbs, except for one combination that revealed additive effects. The lowest effective antibody concentration for 50% viral neutralization (EC50) and EC90 were achieved with combinations of MAbs b12, 2F5, 2G12, and the anti-V3 MAb 694/98D. Depending on the combination regimen, the concentration of MAbs required to reach 90% virus neutralization was reduced approximately 2- to 25-fold as compared to the dose requirement of individual MAbs to produce the same effect. Synergy of the combination regimens implies that combinations of antibodies may have a role in passive immunoprophylaxis against HIV-1. The ability of SHIV to replicate in rhesus macaques will allow us to test such approaches in vivo.

Animals↗