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Biomedical subjects

T C Chan

Publications and source records attributed to T C Chan.

At least 73 records · Page 4Linked to original sources
PubMed1991

Perceiving the vertical distances of surfaces by means of a hand-held probe.

Nine experiments were conducted on the haptic capacity of people to perceive the distances of horizontal surfaces solely on the basis of mechanical stimulation resulting from contacting the surfaces with a vertically held rod. Participants touched target surfaces with rods inside a wooden cabinet and reported the perceived surface location with an indicator outside the cabinet. The target surface, rod, and the participant's hand were occluded, and the sound produced in exploration was muffled. Properties of the probe (length, mass, moment of inertia, center of mass, and shape) were manipulated, along with surface distance and the method and angle of probing. Results suggest that for the most common method of probing, namely, tapping, perceived vertical distance is specific to a particular relation among the rotational inertia of the probe, the distance of the point of contact with the surface from the probe's center of percussion, and the inclination at contact of the probe to the surface. They also suggest that the probe length and the distance probed are independently perceivable. The results were discussed in terms of information specificity versus percept-percept coupling and parallels between selective attention in haptic and visual perception.

Adult↗
PubMed1991

Residues of polychlorinated biphenyls (PCBs) in fish, water and sediment from Shing Mun River.

The level and pattern of contamination by polychlorinated biphenyls (PCBs) were investigated in tilapia, Oreochromis mossambicus (Peters), sediment, and water from the Shing Mun River. The range of total PCBs was 12.9 ng/g to 181.6 ng/g wet weight in tilapia, 12.7 ng/g to 46.0 ng/g freeze-dried weight in sediment, and 3.8 ng/L to 13.6 ng/L in water. The effect of biomagnification was also observed, PCB concentrations increased from water to sediment to tilapia. PCB congeners occurred in such a way that lower chlorinated PCBs comprised a higher fraction of the total PCBs in water, sediment, and tilapia muscle, whereas higher chlorinated PCBs were more commonly found only in tilapia.

Animals↗
PubMed1990

Role of hypoxanthine and thymidine in determining methotrexate plus dipyridamole cytotoxicity.

The nucleoside transport inhibitor dipyridamole can potentiate the cytotoxicity of methotrexate by a mechanism that was thought to be related to the inhibition of thymidine salvage. In human ovarian carcinoma cells thymidine only partly reversed the in vitro cytotoxicity of methotrexate plus dipyridamole at sub-millimolar concentrations, above which the cytotoxicity of thymidine itself became evident. Hypoxathine with thymidine, or hypoxanthine alone at a higher concentration, completely reversed methotrexate and methotrexate plus dipyridamole cytotoxicity. The effects of dipyridamole on cellular cyclic adenosine monophosphate (cAMP) levels and on 3H-methotrexate efflux in 2008 cells were examined. At 10 mumol/l, dipyridamole did not alter cAMP content or methotrexate influx in ovarian carcinoma cells, but reduced the rate of efflux of 3H-methotrexate by 25%. In Chinese hamster ovary cells and their folylpolyglutamyl synthase-deficient variant AUX B1, the reduced methotrexate efflux by dipyridamole was not due to increased polyglutamation, since increased retention was observed in both cell lines. The data support the hypothesis that dipyridamole potentiated the activity of methotrexate by inhibiting the salvage of hypoxanthine, and to a lesser extent, that of thymidine. The ability of dipyridamole to increase the cellular retention of methotrexate was probably a non-specific action of dipyridamole on the cell membrane, and may have a role in the observed synergy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Dipyridamole enhancement of etoposide sensitivity.

Dipyridamole (DPM) enhanced the sensitivity of human ovarian carcinoma 2008 cells to etoposide (VP-16) producing a 5.5-fold reduction in 50% inhibitory concentration at a DPM concentration of 20 microM. This interaction was shown to be truly synergistic by isobologram and median effect analysis. DPM increased the steady-state VP-16 content of 2008 cells; a DPM concentration of 4 microM increased VP-16 content by 2-fold. DPM was 25 times less potent when cells were incubated in human plasma. In tissue culture medium 96% of the DPM was free, whereas in plasma only 15% was non-protein bound. DPM did not displace VP-16 from proteins under either condition. DPM did not increase the initial influx of VP-16 but did inhibit the initial efflux, reducing the efflux rate constant by 27%. DPM had no effect on the later stages of drug efflux, nor did it irreversibly bind VP-16 in the cell. The effect of DPM was evident within 1 min; once removed, the effect disappeared within 2 min. DPM is a potent nucleoside membrane transport inhibitor and can also inhibit cyclic AMP (cAMP) phosphodiesterase in platelets. Nitrobenzylthioinosine, another nucleoside transport inhibitor which competes for binding with DPM, did not enhance sensitivity to VP-16 or increase VP-16 cellular accumulation and did not block the effect of DPM. In 2008 cells, DPM did not increase cAMP; when cAMP was increased by incubation with dibutyryl cyclic 3':5'-AMP, there was no synergy with VP-16. The results indicate that enhanced sensitivity to VP-16 was not due to an effect of DPM on the protein binding of VP-16 or on cellular cAMP and suggest that it is not directly related to inhibition of nucleoside transport. This effect appears to be a newly identified mechanism of action for this agent.

Blood Proteins↗
PubMed1989

Augmentation of 1-beta-D-arabinofuranosylcytosine cytotoxicity in human tumor cells by inhibiting drug efflux.

Dipyridamole is a potent inhibitor of membrane nucleoside transport into mammalian cells. Since the membrane transporter mediates both the influx and the efflux of nucleosides, dipyridamole should be able to block nucleoside efflux from cells as well. In human ovarian carcinoma cells (2008) and promyelocytic leukemia cells (HL60), we observed that sequential treatment with 20 microM dipyridamole 2 h after their initial exposure to varying concentrations of 1-beta-D-arabinofuranosylcytosine (ara-C) increased the cytotoxicity of this nucleoside analogue by 100 to 300% at all drug concentrations tested. In washout experiments in which cells were exposed to radiolabeled ara-C for 2 h and reincubated in fresh medium, the presence of 20 microM dipyridamole in the reincubation medium resulted in significantly elevated levels of intracellular radioactivity at the end of a 24-h period. High performance liquid chromatography analyses of cellular nucleotide pools during this 24-h period revealed that cells treated with the sequential ara-C/dipyridamole regimen have 2-to 3-fold higher levels of ara-CTP at all time points studied. Using alkaline elution assays, we measured a 30% increase in DNA strand breaks in cells treated with ara-C followed by dipyridamole when compared to cells treated with ara-C alone, while dipyridamole alone did not produce DNA lesions. ara-C resistance in tumor cells is associated with either the natural substrates competing with ara-C for phosphorylation and incorporation into macromolecules or increased catabolism of the parent drug. Sequential exposure regimens may overcome such tumor resistance by increasing the cellular pools of ara-C and its metabolites. A second advantage to the sequential regimen is that the prolonged retention of ara-C in non-S-phase cells may improve its efficacy. The applicability of such regimens in treating human cancer awaits the results from preclinical efficacy and toxicity trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Calcium-independent growth of human ovarian carcinoma cells.

Evidence in the literature suggests that cancer cell growth in vitro is generally not sensitive to external calcium. A human ovarian carcinoma cell line (SKOV3) retained 60% of its normal growth in Dulbecco modified Eagle's medium (DME) when the calcium concentration was reduced from 3 mM to 10 microM. Chinese hamster ovary cells (CHO) were growth-arrested in media containing less than 500 microM calcium. In low-calcium (10 microM) DME, 10 microM of a calmodulin antagonist W7 inhibited the growth of SKOV3 cells by more than 90%, while 100 microM of its inactive analog W5 was mildly inhibitory (20%). The growth inhibition by W7 was antagonized by increasing calcium concentrations in the culture media, while the inhibition by W5 was calcium-independent. The phorbol ester TPA was also effective in antagonizing W7's growth inhibition in low-calcium DME, suggesting that the W7 effect is mediated via protein kinase C inhibition. SKOV3 total cellular protein kinase C activity was 1.6 times higher than CHO cells when incubated in normal DME. When incubated in low-calcium DME, a large drop in protein kinase C activity in the CHO cells was observed while the enzyme activity was unchanged in the SKOV3 cells. Our data suggest that these human ovarian tumor cells have altered cellular calcium regulatory processes associated with the defective down-regulation of protein kinase C. This defect may confer these cells the ability to proliferate independently of the external calcium concentration. Targeting the cellular signal transduction components may be useful in cancer chemotherapy.

Animals↗
PubMed1989

Unexpected synergy between N-phosphonacetyl-L-aspartate and cytidine against human tumor cells.

Cytidine, a non-toxic endogenous nucleoside, was found unexpectedly to augment the cytotoxicity of a pyrimidine antimetabolite N-phosphonacetyl-L-aspartate (PALA) in human ovarian carcinoma cells. The PALA/cytidine synergy is confirmed here in other human tumor cells (T242 melanoma, HL60 promyelocytic leukemia and SKOV3 ovarian carcinoma) in the cytidine concentration range of 1-10 micromolar. The synergy was not observed in Chinese hamster ovary (CHO) cells. Exogenous uridine (5-50 microM) completely reversed the PALA/cytidine cytotoxicity in a concentration-dependent manner. Measurements of cellular ribonucleotide levels revealed that the PALA treated cells had reduced UTP and CTP pools (10% and 40% of control respectively); and the PALA/cytidine treated cells had elevated CTP and GTP levels while their UTP levels remained at 10% of control. Deoxyribonucleotide levels were unremarkable except for a slight elevation of dCTP in the PALA/cytidine treated cells. Uridine competitively inhibited radioactive cytidine transport into 2008 cells, which may explain its ability to antagonize the PALA/cytidine synergy. These results suggest that the ribonucleotide biosynthetic mechanism is the primary cellular target for PALA/cytidine activity, and that the ratio of ribonucleotides to each other is an important determinant of tumor cell viability. The use of non-cytotoxic nucleosides to augment the activity of antimetabolites may have clinical relevance in cancer therapy.

Antimetabolites, Antineoplastic↗
PubMed1988

Pharmacokinetics of intraperitoneally administered dipyridamole in cancer patients.

The pharmacokinetics of i.p. administered dipyridamole was studied in six patients to explore the feasibility of using this drug as a modulator of antimetabolite activity in extravascular spaces. Infusions of dipyridamole (50 mg/m2 in 2 liters of normal saline) into the peritoneal cavity resulted in peak drug concentrations 5 to 20 times higher in that cavity than in the plasma. The peritoneal decay data for dipyridamole fitted very well to a single compartment open pharmacokinetic model with one exponential term, while the plasma data are adequately described by a single compartment model with two exponentials (a short absorption phase). The mean peritoneal half-life for total extractable dipyridamole was 3.3 +/- 1.9 (SD) h, and the mean peritoneal clearance was 0.4 +/- 0.3 liters/h/m2. The mean plasma half-life of total dipyridamole in our patients was 2.2 +/- 1.2 h, and the mean clearance value was 5.7 +/- 4.7 liters/h/m2. The area under the concentration versus time curve was calculated to be 626 +/- 312 microM-h for the peritoneal cavity and 45 +/- 20 microM-h for the plasma. Using membrane ultrafiltration, we have measured the concentration of free (non-protein bound) dipyridamole in each patient. While the peritoneal clearance values of free and total drug are comparable, the plasma clearance of free dipyridamole was 47 +/- 39 liters/h/m2. This increased plasma clearance resulted in a plasma area under the concentration versus time curve of 8.3 +/- 5.1 microM-h, which suggests minimal systemic exposure. Our data show that instillation of dipyridamole into the peritoneal cavity resulted in much higher local drug exposure than systemic exposure, confirming the feasibility of using this drug to augment antimetabolite activity within the peritoneal cavity. Since dipyridamole is highly protein bound in the plasma but less so in the peritoneal cavity, these data imply that peritoneal exposure to active (free) dipyridamole is far greater than systemic exposure in our patients.

Aged↗
PubMed1988

Uridine pharmacokinetics in cancer patients.

The availability of uridine can alter the sensitivity of tumor cells to antimetabolites such as N-phosphonacetyl-L-aspartic acid (PALA) and acivicin by virtue of the cell's ability to salvage preformed metabolites from its environment. We investigated the pharmacokinetics of physiologically relevant amounts of uridine in cancer patients in a pilot study to further our understanding of uridine metabolism in the human body. Four cancer patients, two males and two females, were given an i.v. bolus of a trace amount of radiolabeled uridine. The nucleoside disappeared from the plasma in a triphasic manner, with initial half-lives of 0.57 +/- 0.28 and 1.79 +/- 0.62 min and a terminal half-life of 17.5 +/- 7.3 min. The volume of distribution was 481 +/- 70 ml/kg, and the plasma uridine clearance was calculated to be 1.70 +/- 0.42 l/min. Simultaneous plasma and bone marrow uridine concentrations were measured in a separate group of seven healthy volunteers. The uridine concentration in plasma was 2.32 +/- 0.58 microM, and that in the bone marrow plasma was 10.44 +/- 5.06 microM. These results suggest a very rapid turnover of uridine in the plasma when the nucleoside is present at physiologic concentrations, and that there is a locally high concentration of uridine available for salvage in the bone marrow.

Adult↗
PubMed1988

Total serum cholesterol and plasma lipoprotein cholesterol concentrations in cord sera of newborns from hispanic mothers with gestational diabetes.

The objective of this research was to determine if gestational diabetes has an impact on the plasma lipoprotein profiles and/or cholesterol content of the plasma lipoproteins in newborns. Very low plus low density lipoproteins and high density lipoproteins in cord sera of newborns from gestational diabetic and non-diabetic mothers were isolated by heparin-affinity chromatography, and the cholesterol content in these plasma lipoprotein fractions were measured with an enzymatic assay. There were no significant differences in baby weights and total serum cholesterol levels between the two experimental groups. High density lipoprotein cholesterol levels (p less than 0.05) were significantly lower while very low plus low density lipoprotein cholesterol concentrations (p less than 0.05), very low plus low density lipoprotein cholesterol/high density lipoprotein cholesterol ratios (p less than 0.025), and total serum cholesterol/high density lipoprotein cholesterol ratios (p less than 0.025) were significantly elevated in newborns of diabetic mothers. These results suggest that gestational diabetes altered neonatal plasma lipoprotein metabolism.

Cholesterol↗
PubMed1987

Phase I trial of combination therapy of cancer with N-phosphonacetyl-L-aspartic acid and dipyridamole.

While N-phosphonacetyl-L-aspartic acid (PALA), an inhibitor of de novo pyrimidine biosynthesis, demonstrated a unique spectrum of activity during preclinical drug evaluation, multiple clinical trials have shown it to possess minimal clinical activity. One explanation for the disappointing results is the possibility that tumor cells are able to utilize circulating uridine in the synthesis of pyrimidines (salvage pathway). Dipyridamole, an inhibitor of nucleoside transport, has been demonstrated experimentally to potentiate the cytotoxicity of PALA significantly. In addition, this agent has a long safety record when used clinically in man. A phase I trial of this two-drug combination was therefore conducted, with a fixed oral dose of dipyridamole (50 mg/m2 every 6 h) and an escalating i.v. dose of PALA administered every 3 weeks. The dose-limiting toxicity with this schedule was diarrhea and abdominal cramping pain at a PALA dose of 3900-4200 mg/m2. Among the 65 patients participating in this trial 4 objective responses (2 partial, 2 minimal) were observed. Because of the potential for unique clinical synergy between PALA and dipyridamole further investigation should be considered.

Adult↗
PubMed1986

Plasma uridine changes in cancer patients treated with the combination of dipyridamole and N-phosphonacetyl-L-aspartate.

Dipyridamole (DP) and N-phosphonacetyl-L-aspartate (PALA) act synergistically in vitro against many cell lines and in vivo against human ovarian carcinoma xenografts. We have conducted a phase I clinical trial of DP p.o. (50 mg/m2, every 6 h) in combination with PALA (starting at 500 mg/m2 i.v. with 300-mg dose escalations). Sixty-five patients were entered into this study, and we have established the maximum tolerated dose of PALA to be 4.5 g/m2 when combined with DP, which is approximately 80% of the previously reported maximum tolerated dose for PALA alone. The observed toxicities of DP plus PALA were mild and were similar to those reported for PALA alone. Bone marrow toxicities were not evident at any PALA dose. Ten patients with a mean pretreatment plasma uridine concentration of 3.49 +/- 1.28 (SD) microM had their plasma uridine reduced to 2.29 +/- 0.70 microM 9 h after DP p.o. A peak plasma DP concentration of 1.86 +/- 0.99 microM was achieved approximately 2 h after p.o. dosing. Nine patients who had a reduced plasma uridine concentration of 2.46 +/- 0.61 microM after 1 week of DP had their plasma uridine further reduced by PALA to 0.87 +/- 0.23 microM 7 h post-PALA. Daily plasma uridine measurements in two patients during their DP treatment confirmed the previously described pattern for Day 1, but the data suggest a slight recovery (15%) in plasma uridine by Day 2. Daily sampling in two other patients after a single PALA dose of 4.2 g/m2 showed that their plasma uridine declined 5 h after the PALA dose and remained depressed for 6 days in one patient and 11 days in the other. These results suggest that DP worked in synergy with PALA to lower circulating uridine in cancer patients. The mechanism for the ability of DP to reduce plasma uridine is not known, but there is evidence that DP can inhibit cellular efflux of uridine as well as its uptake. DP may reduce plasma nucleoside pools in addition to blocking nucleoside salvage and therefore have general applicability in other chemotherapy regimens.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1985

Differential intraarterial pressure recordings from different arteries in the rat.

Intraarterial pressures were recorded from five different sites in pentobarbital anesthetized rats. Simultaneous recordings were made from the brachial artery, carotid artery, femoral artery, tail artery, and a small end-branch of the superior mesenteric artery under basal conditions and under vasoconstrictor and vasodilator influences to find out whether similar mean arterial pressures (MAP) can be recorded from the various sites. It was found that MAP of proximal arteries (brachial and carotid) is higher than the MAP recorded from more distal arteries (mesenteric, tail, and femoral). A pressure difference of 5-6 mm Hg was found to exist from the level of the carotid artery to that of the femoral artery during all experimental conditions. Our results indicate that the same artery should always be used to compare MAP between different rats. Moreover, calculations of arterial resistance (MAP/BF) of most vascular beds in the rat, using MAP values obtained from the tail or the femoral artery, as are commonly done in physiologic or pharmacologic studies, can result in slightly lower resistance values than the true resistance. To obtain true arterial resistance of any vascular bed, one has to use MAP recorded at the particular vascular bed for the calculation of resistance.

Animals↗
PubMed1985

Modulation of the activity of PALA by dipyridamole.

PALA is thought to inhibit an early step in de novo pyrimidine synthesis, causing depletion of intracellular pyrimidine nucleotides. Dipyridamole, a nucleoside transport inhibitor which can block restoration of nucleotide levels via the salvage pathway, was tested for its ability to augment the cytotoxicity of PALA against normal and malignant human cells in vitro. At the clinically relevant concentration of 1 microM, dipyridamole increased the cytotoxicity of PALA against a melanoma, a colon carcinoma, a promyelocytic leukemia (HL-60), and normal marrow (CFU-GM) in clonogenic assays. Dipyridamole produced 50% inhibition of uridine uptake in these cells at concentrations of less than 0.1 microM and reduced the LD50 of PALA by approximately 50% in mice. These results indicate that dipyridamole can markedly potentiate the activity of PALA in vitro and in vivo.

Animals↗
PubMed1985

Mechanism of synergy between N-phosphonacetyl-L-aspartate and dipyridamole in a human ovarian carcinoma cell line.

Previous results from our laboratory have shown that the nucleoside transport inhibitor dipyridamole (DP) markedly augmented both the in vitro and in vivo activities of the pyrimidine antimetabolite N-phosphonacetyl-L-aspartate (PALA). In a human ovarian carcinoma cell line (2008), DP increased the activity of PALA by 1 to 2 logs in growth rate and clonogenic assays while exhibiting no cytotoxicity of its own. The concentration of DP used (1 microM) in these assays resulted in over 80% reduction in uridine uptake in the 2008 cells at the end of 1 h. The activity of PALA and PALA plus DP was completely antagonized by the addition of exogenous uridine in a dose-dependent manner. Addition of other nucleosides to concentrations as high as 1000 microM failed to rescue the ovarian cells from the drug combination, and combining two nucleosides together did not antagonize PALA and PALA plus DP activity to any greater extent. Cellular nucleotide pool analysis by anion-exchange high-performance liquid chromatography revealed that dipyridamole further reduced the already depressed uridine triphosphate and cytidine triphosphate pools of cells exposed to PALA, while the guanosine triphosphate pool was slightly elevated. Uridine supplementation resulted in partial replenishment of the uridine triphosphate and cytidine triphosphate pools, but the absolute levels remained below control values. The acute drug-induced changes in nucleotide pools in 2008 xenografts growing in athymic mice paralleled those observed in vitro. Evidence presented here supports the ability of DP to potentiate PALA activity against a human ovarian carcinoma cell line. The mechanism of synergy relates to the inhibition of pyrimidine salvage in the tumor cells via the blockade of uridine uptake.

Antineoplastic Agents↗
PubMed1984

Lack of transplacental infection with scrub typhus organisms in laboratory mice.

Female mice were inoculated with either a virulent or avirulent strain of Rickettsia tsutsugamushi before (1 month and 1 week) or after (approximately 10 days) impregnation. From each group, two pregnant mothers were killed on day 20 post-impregnation, and fetuses and placentas were examined for rickettsiae. Organisms were isolated from 80% of placentas but not from the fetuses. Immediately following parturition, litters from 50% of the infected mothers were exchanged with litters from uninfected mothers. In all cases, no scrub typhus rickettsiae were found in the litters examined on days 1, 7, and 30 postpartum, and no antibody was found in sera collected 1 and 2 months postpartum.

Animals↗