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Biomedical subjects

M Guo

Publications and source records attributed to M Guo.

At least 19 recordsLinked to original sources
PubMed2007

A likelihood approach to estimating sensitivity and specificity for binocular data: application in ophthalmology.

Binocular data typically arise in ophthalmology where pairs of eyes are evaluated, through some diagnostic procedure, for the presence of certain diseases or pathologies. Treating eyes as independent and adopting the usual approach in estimating the sensitivity and specificity of a diagnostic test ignores the correlation between eyes. This may consequently yield incorrect estimates, especially of the standard errors. The paper proposes a likelihood-based method of accounting for the correlations between eyes and estimating sensitivity and specificity using a model for binocular or paired binary outcomes. Estimation of model parameters via maximum likelihood is outlined and approximate tests are provided. The efficiency of the estimates is assessed in a simulation study. An extension of the methodology to the case of several diagnostic tests, or the same test measured on several occasions, which arises in multi-reader studies, is given. A further extension to the case of multiple diseases is outlined as well. Data from a study on diabetic retinopathy are analysed to illustrate the methodology.

Canada↗
PubMed2006

Identification of mutations that disrupt phosphorylation-dependent nuclear export of cyclin D1.

Although cyclin D1 is overexpressed in a significant number of human cancers, overexpression alone is insufficient to promote tumorigenesis. In vitro studies have revealed that inhibition of cyclin D1 nuclear export unmasks its neoplastic potential. Cyclin D1 nuclear export depends upon phosphorylation of a C-terminal residue, threonine 286, (Thr-286) which in turn promotes association with the nuclear exportin, CRM1. Mutation of Thr-286 to a non-phosphorylatable residue results in a constitutively nuclear cyclin D1 protein with significantly increased oncogenic potential. To determine whether cyclin D1 is subject to mutations that inhibit its nuclear export in human cancer, we have sequenced exon 5 of cyclin D1 in primary esophageal carcinoma samples and in cell lines derived from esophageal cancer. Our work reveals that cyclin D1 is subject to mutations in primary human cancer. The mutations identified specifically disrupt phosphorylation of cyclin D1 at Thr-286, thereby enforcing nuclear accumulation of cyclin D1. Through characterization of these mutants, we also define an acidic residue within the C-terminus of cyclin D1 that is necessary for recognition and phosphorylation of cyclin D1 by glycogen synthase kinase-3 beta. Finally, through construction of compound mutants, we demonstrate that cell transformation by the cancer-derived cyclin D1 alleles correlates with their ability to associate with and activate CDK4. Our data reveal that cyclin D1 is subject to mutations in primary human cancer that specifically disrupt phosphorylation-dependent nuclear export of cyclin D1 and suggest that such mutations contribute to the genesis and progression of neoplastic growth.

Alleles↗
PubMed2006

Hypoxia-mimetic agents desferrioxamine and cobalt chloride induce leukemic cell apoptosis through different hypoxia-inducible factor-1alpha independent mechanisms.

Hypoxia presents pro-apoptotic and anti-apoptotic biphasic effects that appear to be dependent upon cell types and conditions around cells. The substantial reports demonstrated that commonly used hypoxia-mimetic agents cobalt chloride (CoCl(2)) and desferrioxamine (DFO) could also induce apoptosis in many different kinds of cells, but the mechanism was poorly understood. In this work, we compare the apoptosis-inducing effects of these two hypoxia-mimetic agents with acute myeloid leukemic cell lines NB4 and U937 as in vitro models. The results show that both of them induce these leukemic cells to undergo apoptosis with a loss of mitochondrial transmembrane potentials (DeltaPsi m), the activation of caspase-3/8 and the cleavage of anti-apoptotic protein Mcl-1, together with the accumulation of hypoxia-inducible factor-1 alpha (HIF-1alpha) protein, a critical regulator for the cellular response to hypoxia. Metavanadate and sodium nitroprusside significantly abrogate DFO rather than CoCl(2)-induced mitochondrial Delta Psi m collapse, caspase-3/8 activation, Mcl-1 cleavage and apoptosis, but they fail to influence DFO and CoCl(2)-induced HIF-1alpha protein accumulation. Moreover, inducible expression of HIF-1alpha gene dose not alter DFO and CoCl(2)-induced apoptosis in U937 cells. In conclusion, these results propose that although both DFO and CoCl(2)-induced leukemic cell apoptosis by mitochondrial pathway-dependent and HIF-1alpha-independent mechanisms, DFO and CoCl(2)-induced apoptosis involves different initiating signal pathways that remain to be investigated.

Base Sequence↗
PubMed2005

The receptor activator of nuclear factor-kappaB ligand inhibitor osteoprotegerin is a bone-protective agent in a rat model of chronic renal insufficiency and hyperparathyroidism.

Osteoprotegerin (OPG) acts by neutralizing the receptor activator of nuclear factor-kappaB ligand (RANKL), the primary mediator of osteoclast differentiation, function, and survival. We examined whether OPG could affect the bone loss associated with chronic kidney disease (CKD) in a rodent model of CKD and secondary hyperparathyroidism (SHPT). SHPT was induced in rats by 5/6 nephrectomy (5/6 Nx) and a 1.2% P/0.6% Ca(2+) diet. Starting 1 week after 5/6 Nx, rats were treated with vehicle (veh) or OPG-Fc (3 mg/kg, intravenously) every 2 weeks for 9 weeks. At baseline, 3, 6, and 9 weeks, blood was taken and bone mineral density (BMD) and bone mineral content (BMC) were assessed by dual-energy X-ray absorptiometry. Serum parathyroid hormone (sPTH) levels reached 912 pg/ml in 5/6 Nx rats vs. 97 pg/ml in shams at 9 weeks. OPG-Fc had no effect on sPTH or Ca(2+) levels throughout the 9-week study, indicating that SHPT was a renal effect independent of bone changes. At 3 weeks, 5/6 Nx-veh rats had osteopenia compared with sham-veh rats and 5/6 Nx-OPG-Fc rats had significantly higher percent changes in whole-body BMC, leg BMD, and lumbar BMD versus 5/6 Nx-veh rats. By 6-9 weeks, elevated sPTH was associated with reversal of bone loss and osteitis fibrosa in the proximal tibial metaphysis. OPG-Fc decreased this sPTH-driven high bone turnover, resulting in augmented thickness of proximal tibial trabeculae in 5/6 Nx rats. Thus, RANKL inhibition with OPG-Fc can block the deleterious effects of continuously elevated sPTH on bone, suggesting that RANKL may be an important therapeutic target for protecting bone in patients with CKD and SHPT.

Absorptiometry, Photon↗
PubMed2005

Effect of an acid mine drainage effluent on phytoplankton biomass and primary production at Britannia Beach, Howe Sound, British Columbia.

We investigated the effect of acid mine drainage (AMD) from an abandoned copper mine at Britannia Beach (Howe Sound, BC, Canada) on primary productivity and chlorophyll a levels in the receiving waters of Howe Sound before, during, and after freshet from the Squamish River. Elevated concentrations of copper (integrated average through the water column >0.050 mgl(-1)) in nearshore waters indicated that under some conditions a small gyre near the mouth of Britannia Creek may have retained the AMD from Britannia Creek and from a 30-m deep water outfall close to shore. Regression and correlation analyses indicated that copper negatively affected primary productivity during April (pre-freshet) and November (post-freshet). Negative effects of copper on primary productivity were not supported statistically for July (freshet), possibly because of additional effects such as turbidity from the Squamish River. Depth-integrated average and surface chlorophyll a were correlated to copper concentrations in April. During this short study we demonstrated that copper concentrations from the AMD discharge can negatively affect both primary productivity and the standing stock of primary producers in Howe Sound.

Biomass↗
PubMed2005

Human exposure and health risk of alpha-, beta-, gamma- and delta-hexachlorocyclohexane (HCHs) in Tianjin, China.

The dynamic exposures to HCHs of individuals born between the years 1913 and 1993 in Tianjin have been simulated by connecting a fugacity model (IV) with a multimedia exposure model. Ingestion is the most important pathway for human beings to take up HCHs, and concentrations in the human body correlate with body weight changes. Accumulations of HCHs were derived assuming that the degradation in human body behaved linearly. The health risk of exposure to HCHs was measured using cancer risk and loss of life expectancy (LLE), and LLE was modified from its original definition to incorporate a dynamic calculation that takes variances in exposure into account. Monte-Carlo simulations were run to analyze the uncertainties of the model.

Age Factors↗
PubMed2005

Surface-enhanced Raman spectroscopy using silver-coated porous glass-ceramic substrates.

Surface-enhanced Raman scattering (SERS) has been studied using a silver-coated porous glass-ceramic material as a new type of substrate. The porous glass-ceramic is in the CaO-TiO2-P2O5 system prepared by controlled crystallization and subsequent chemical leaching of the dense glass-ceramic, leaving a solid skeleton with pores ranging in size from 50 nm to submicrometer. Silver was coated on the surface of the porous glass-ceramic by radio frequency (RF) sputtering or e-beam evaporation in vacuum. SERS spectra of excellent quality were obtained from several dyes and carboxylic acid molecules, including rhodamine 6G, crystal violet, isonicotinic acid, and benzoic acid, using this new substrate. This new substrate showed a good compatibility with these molecules. The porous glass ceramic with a nanometer-structured surface accommodated both test molecules and silver film. The absorbed molecules were therefore better interfaced with silver for surface-enhanced Raman scattering.

Benzoic Acid↗
PubMed2005

Changes in chemical composition of Alxa bactrian camel milk during lactation.

Changes in chemical composition of Alxa bactrian camels reared in Inner Mongolia (China) during lactation were investigated. Colostrum and milk samples from 10 nomadic female camels in their first season of lactation were collected periodically from parturition until 90 d postpartum (PP). The average contents of gross composition were 14.23% protein, 4.44% lactose, 0.27% fat, 0.77% ash, and 20.16% total solids in colostrum at 2 h PP, and the respective mean values were 3.55, 4.24, 5.65, 0.87, and 14.31% for regular milk on d 90. A 15-fold increase was shown in fat content during the first 24 h, whereas a sharp decrease was shown during the first 12 h of lactation in protein, ash, and total solids contents. Variation in lactose content was small (4.24 to 4.71%) throughout the study period. Total N, nonprotein N, casein N, and whey protein N were found to be 2.23, 0.06, 0.86, and 1.31 g/100 mL for the colostrum at 2 h PP; and 0.56, 0.04, 0.45, and 0.07 g/100 mL for the milk at 90 d PP. Percentages of caseins increased steadily, whereas whey proteins declined gradually until 3 mo of lactation. Gas liquid chromatography analysis of milk fat showed that the content of even-numbered saturated fatty acids (C12:0-C18:0) in camel colostrum (2 h to 7 d PP) was lower than that of regular milk (15 to 90 d PP). The predominant saturated fatty acids were C14:0, C16:0, and C18:0, regardless of the stage of lactation. There was a considerable level of polyunsaturated fatty acids (mainly C18:1) in Alxa camel's milk fat. The levels of Ca, P, Na, K, and Cl were 222.58, 153.74, 65.0, 136.5, and 141.1 mg/100 g, respectively, at 2 h PP; the values of the minerals were 154.57, 116.82, 72.0, 191.0, and 152.0 mg/100 g, respectively, for the regular milk on d 90. The levels of vitamins A, C, E, B1, B2, B6, and D were 0.97, 29.60, 1.45, 0.12, 1.24, 0.54 mg/L, and 640 IU/L, respectively, in Alxa camel milk at 90 d PP. Vitamin A and C contents were higher and vitamins E and B1 were lower than those in colostrum. Sodium dodecyl sulfate-PAGE and densitometry results demonstrated that Alxa camel colostrum is rich in immunoglobulins, serum albumin, and 2 unknown fractions, which are reduced in amount (%) within 2 d of lactation. It seems that there is lack of beta-lactoglobulin in Alxa camel milk, whereas casein and -lactalbumin start at a low level and increase gradually until they reach their regular levels in the milk.

Animals↗
PubMed2003

Detection of human papillomavirus-16 in ovarian malignancy.

Human papillomavirus is the causal factor for cervical cancer. However, the role of HPV infection in ovarian cancer is unclear. This study aimed to determine the presence of human papillomavirus-16 (HPV-16) in ovarian cancer tissues. Archived human ovarian cancer tissues (N=54 cases, 50 are epithelial cancer, four are nonepithelial cancer) embedded in paraffin blocks were used. Controls are 30 nonmalignant ovarian tissue blocks. In situ hybridisation (ISH) and immunohistochemistry (IHC) were used to detect the presence of HPV-16 and p53 expression. In all, 52 or 36% of the epithelial ovarian tumours detected by ISH or IHC, respectively, were HPV-16 E6 positive. In contrast, only 6.7% of normal ovarian tissues were HPV-16 positive proved by ISH. Human papillomavirus-16 infection was significantly higher in cancer tissues compared to controls with an odds ratio of 16.7 (95% confidence interval [CI]=3.2-71.4, P<0.01). No significant correlation between HPV-16 infection and histological types of cancer was found (P>0.05). p53 gene expression was detected in 42% epithelial ovarian cancers. No correlation between p53 expression and HPV-16 infection was found. The results showed the presence of HPV-16 E6 in ovarian carcinoma, suggesting that HPV infection might play a role in ovarian carcinogenesis.

Adult↗
PubMed2001

Molecular characteristics of non-small cell lung cancer.

We used hierarchical clustering to examine gene expression profiles generated by serial analysis of gene expression (SAGE) in a total of nine normal lung epithelial cells and non-small cell lung cancers. Separation of normal and tumor, as well as histopathological subtypes, was evident by using the 3,921 most abundant transcript tags. This distinction remained when only 115 highly differentially expressed tags were used. Furthermore, these 115 transcript tags clustered into groups suggestive of the unique biological and pathological features of the different tissues examined. Adenocarcinomas were characterized by high-level expression of small airway-associated or immunologically related proteins, whereas squamous cell carcinomas overexpressed genes involved in cellular detoxification or antioxidation. The messages of two p53-regulated genes, p21(WAF1/CIP1) and 14-3-3final sigma, were consistently underexpressed in the adenocarcinomas, suggesting that the p53 pathway itself might be compromised in this cancer type. Gene expression patterns observed by SAGE were consistent with results obtained by quantitative real-time PCR or cDNA array analyses by using a total of 43 lung tumor and normal samples. Thus, although derived from only a few tissue libraries, gene expression profiles obtained by using SAGE most likely represent an unbiased yet distinctive molecular signature for the most common forms of human lung cancer.

Base Sequence↗
PubMed2001

DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis.

Cancer cells have aberrant patterns of DNA methylation including hypermethylation of gene promoter CpG islands and global demethylation of the genome. Genes that cause familial cancer, as well as other genes, can be silenced by promoter hypermethylation in sporadic tumors, but the methylation of these genes in tumors from kindreds with inherited cancer syndromes has not been well characterized. Here, we examine CpG island methylation of 10 genes (hMLH1, BRCA1, APC, LKB1, CDH1, p16(INK4a), p14(ARF), MGMT, GSTP1 and RARbeta2) and 5-methylcytosine DNA content, in inherited (n = 342) and non-inherited (n = 215) breast and colorectal cancers. Our results show that singly retained alleles of germline mutated genes are never hypermethylated in inherited tumors. However, this epigenetic change is a frequent second "hit", associated with the wild-type copy of these genes in inherited tumors where both alleles are retained. Global hypomethylation was similar between sporadic and hereditary cases, but distinct differences existed in patterns of methylation at non-familial genes. This study demonstrates that hereditary cancers "mimic" the DNA methylation patterns present in the sporadic tumors.

Breast Neoplasms↗
PubMed2001

Suppression of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated CYP1A1 and CYP1B1 induction by 12-O-tetradecanoylphorbol-13-acetate: role of transforming growth factor beta and mitogen-activated protein kinases.

The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) enhances or suppresses the transcriptional activation of CYP1A1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in a cell/tissue-specific manner. The basis for these effects is not known. Exposure of the immortalized human breast epithelial cell line MCF10A-Neo to TPA at the time of, or up to 12 hr prior to, the addition of TCDD strongly suppressed the transcriptional activation of CYP1A1 and CYP1B1 (IC(50) approximately 0.5 nM). A recent study (Carcinogenesis 2000;21:1303-12) demonstrated that TPA-treated MCF10A-Neo cells rapidly activate the latent transforming growth factor beta (TGFbeta) in the serum used to supplement the culture medium. The suppressive effects of TPA on CYP1A1 induction by TCDD in MCF10A-Neo cultures could be partially suppressed by: (a) co-incubation of TCDD + TPA-treated cultures with a neutralizing TGFbeta pan antibody; (b) prior removal of latent TGFbeta from the culture medium; or (c) switching cultures to serum- and growth factor-free medium immediately before the addition of TPA and TCDD. Exposure of cultures to TPA 24-48 hr prior to subsequent TPA + TCDD treatment not only inhibited the suppressive effects of TPA, but markedly enhanced CYP1A1 mRNA accumulation. TPA caused a rapid and protracted activation of extracellular signal-regulated kinases (ERKs). Pretreatment of cultures with the mitogen-activated protein kinase kinase (MEK) inhibitor PD184352 [2-(2-chloro-4-iodo-phenylamino)-N-cyclopropyl-methoxy-3,4-difluoro-benzamide] completely inhibited ERK activation by TPA. However, PD184352 did not prevent the suppressive effects of TPA on CYP1A1 activation by TCDD. These studies demonstrate that TPA initiates protein kinase C-dependent, ERK-independent processes that suppress CYP1A1 activation by TCDD in MCF10A-Neo cells. Furthermore, TGFbeta mediates a small portion of this suppressive activity.

Aryl Hydrocarbon Hydroxylases↗
PubMed2001

Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo.

Dendritic cells (DCs) have the capacity to initiate immune responses, but it has been postulated that they may also be involved in inducing peripheral tolerance. To examine the function of DCs in the steady state we devised an antigen delivery system targeting these specialized antigen presenting cells in vivo using a monoclonal antibody to a DC-restricted endocytic receptor, DEC-205. Our experiments show that this route of antigen delivery to DCs is several orders of magnitude more efficient than free peptide in complete Freund's adjuvant (CFA) in inducing T cell activation and cell division. However, T cells activated by antigen delivered to DCs are not polarized to produce T helper type 1 cytokine interferon gamma and the activation response is not sustained. Within 7 d the number of antigen-specific T cells is severely reduced, and the residual T cells become unresponsive to systemic challenge with antigen in CFA. Coinjection of the DC-targeted antigen and anti-CD40 agonistic antibody changes the outcome from tolerance to prolonged T cell activation and immunity. We conclude that in the absence of additional stimuli DCs induce transient antigen-specific T cell activation followed by T cell deletion and unresponsiveness.

Animals↗
PubMed2001

Important ECG diagnosis-aiding indices of ventricular septal defect children with or without congestive heart failure.

In this paper we perform a statistical study of the conventional RR intervals and two newly defined PR' and RT intervals of ECG data. A quadratic classification rule is applied to extract several important ECG diagnosis-aiding indices among normal children and children with ventricular septal defect (VSD) with or without congestive heart failure (CHF). The results show that certain statistics computed from PR', RR and RT intervals are important diagnosis-aiding indices. Best classification vectors are searched for pairwise classification. Two methods, minimum distance criterion and a two-stage classification procedure, are considered for three-way classification. Furthermore, logistic regression models based on transformations of these important diagnosis-aiding indices are proposed. The receiver operating characteristic curves of the proposed models show better performance than those of linear and quadratic logistic models. In order to proceed with this study, a computer algorithm to automatically detect the three intervals is developed and the related ECG data are collected and analysed. The algorithm is also enhanced with an outlier detection procedure for the automatic measurements of the PR' and RT intervals.

Algorithms↗
PubMed2001

Combination nonviral interleukin 2 and interleukin 12 gene therapy for head and neck squamous cell carcinoma.

OBJECTIVE: To determine the feasibility and efficacy of combination nonviral lipid-formulated murine interleukin 2 (mIL-2) and polymer-formulated murine interleukin 12 (mIL-12) gene therapy for head and neck squamous cell carcinoma (HNSCC) in a murine model. METHODS: Randomized, controlled studies in a murine HNSCC model. Tumors were established in the floor of mouth in C3H/HeJ immunocompetent mice. Established tumors were directly injected with lipid-formulated mIL-2 and polymer-formulated mIL-12 alone and in combination. Antitumor responses, cytokine expression, and natural killer cell and cytolytic T-lymphocyte activity were assayed. RESULTS: The use of combined mIL-2 and mIL-12 gene therapy resulted in significant antitumor effects, compared with each of the single-cytokine and no-treatment (control) groups (P =.01 to P =.02). Tumors treated with the formulated cytokine genes showed an increased level of the corresponding proteins and decreased level of transforming growth factor beta (TGF-beta) expression. Combined mIL-2 and mIL-12 treatment consistently produced the greater activation of cytolytic T-lymphocyte and natural killer cells than did single-cytokine treatment or other controls at all concentrations tested. Augmented immune responses correlated with clinical antitumor effects. CONCLUSIONS: The nonviral gene delivery system was well tolerated, and combined mIL-2 and mIL-12 gene transfer generated potent antitumor immune responses against HNSCC in our murine model. Combined nonviral IL-2 and IL-12 gene therapy may have great potential as a primary or adjuvant treatment for HNSCC in humans.

Adjuvants, Immunologic↗
PubMed2001

Detection and molecular characterization of cultivable caliciviruses from clinically normal mink and enteric caliciviruses associated with diarrhea in mink.

Enteric caliciviruses are emerging pathogens responsible for diarrhea or gastroenteritis in their respective hosts. In this report, mink enteric caliciviruses (MEC) were detected in feces from diarrheic mink by both immune electron microscopy (IEM) and RT-PCR using a broadly reactive primer pair (p289/290) targeting the highly conserved RNA polymerase regions of the enteric caliciviruses, Norwalk-like viruses (NLVs) and Sapporo-like viruses (SLVs). The MEC possess classical caliciviral morphology with typical cup-shaped depressions on the viral surface. Sequence analyses based on nucleotide and predicted amino acid (aa) sequences of the RT-PCR products indicated that MEC is most closely related genetically to SLVs of humans and animals. The MEC shared the highest aa identities (64-71%) in the RNA polymerase region with both human SLVs and the porcine enteric calicivirus (PEC) Cowden strain SLV, indicating that MEC may belong to an individual genogroup or subgroup in the SLV genus. The MEC shared only limited aa identities in the RNA polymerase region with vesiviruses (40-51%) and NLVs (29-33%). The RNA polymerase regions of the cultivable, non-enteric mink caliciviruses (MCV) were also amplified by RT-PCR using the primer pair Pol1/Pol3 based on sequences of vesiviruses, and the primer pair p289/290. Sequence analysis indicated that these MCV shared higher aa identities in the RNA polymerase region with vesiviruses (58-81%) than with SLVs (43-51%) including the MEC, lagoviruses (35-37%) and NLVs (27-35%), suggesting that they are most closely related genetically to vesiviruses. The MEC associated with diarrhea in mink are morphologically similar to but are genetically distinct from the cultivable MCV and likely represent a new member of the SLV genus.

Animals↗
PubMed2001

Titanium(IV) targets phosphoesters on nucleotides: implications for the mechanism of action of the anticancer drug titanocene dichloride.

Abstract Reactions between the anticancer drug titanocene dichloride (Cp2TiCl2) and various nucleotides and their constituents in aqueous solution or N,N-dimethylformamide (DMF) have been investigated by 1H and 31P NMR spectroscopy and in the solid state by IR spectroscopy. In aqueous solution over the pH* (pH meter reading in D2O) range 2.3-6.5, CMP forms one new species with Ti(IV) bound only to the phosphate group. In acidic media at pH*<4.6, three species containing titanocene bound to the phosphate group of dGMP, AMP, dTMP and UMP are formed rapidly. The bases also appear to influence titanocene binding. Only one of these Ti(IV)-bound species can be detected in the pH* range of 4.6-6.5 in each case. The order of reactivity towards Cp2TiCl2(aq) at pH* ca. 3 is GMP>TMP approximately AMP > CMP. At pH* > 7.0, hydrolysis of Cp2TiCl2 predominated and little reaction with the nucleotides was observed. Binding of deoxyribose 5'-phosphate and 4-nitrophenyl phosphate to Cp2TiCl2(aq) via their phosphate groups was detected by 31P NMR spectroscopy, but no reaction between Cp2TiCl2(aq) and deoxyguanosine, 9-ethylguanine or deoxy-D-ribose was observed in aqueous solution. The nucleoside phosphodiesters 3',5'-cyclic GMP and 2',3'-cyclic CMP did not react with Cp2TiCl2(aq) in aqueous solution; however, in the less polar solvent DMF, 3',5'-cyclic GMP coordination to [Cp2Ti]2+ via its phosphodiester group was readily observed. Binding of titanocene to the phosphodiester group of the dinucleotide GpC was also observed in DMF by 31P NMR. The nucleoside triphosphates ATP and GTP reacted more extensively with Cp2TiCl2(aq) than their monophosphates; complexes with bound phosphate groups were formed in acidic media and to a lesser extent at neutral pH. Cleavage of phosphate bonds in ATP (and GTP) by Cp2TiCl2(aq) to form inorganic phosphate, AMP (or GMP) and ADP (or GDP) was observed in aqueous solutions. In addition, titanocene binding to ATP was not inhibited by Mg(II), but the ternary complex titanocene-ATP-Mg appeared to form. These reactions contrast markedly with those of the drug cisplatin, which binds predominantly to the base nitrogen atoms of nucleotides and only weakly to the phosphate groups. The high affinity of Ti(IV) for phosphate groups may be important for its biological activity.

Adenosine Monophosphate↗