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Financing, Government↗
Biomedical subjects
T C Chan
Publications and source records attributed to T C Chan.
Synergism between dipyridamole and cisplatin in human ovarian carcinoma cells in vitro.
Dipyridamole (DPM), a nucleoside membrane transport inhibitor, enhanced the cytotoxicity of cisplatin (DDP) for human ovarian carcinoma 2008 cells by a factor of 4.7 +/- 0.4-fold (mean +/- SD) and for the 10-fold DDP-resistant 2008/C13*5.25 subline by a factor of 5.8 +/- 2.7-fold. This interaction was shown to be truly synergistic by isobologram and median effect analysis. DPM enhancement of DDP cytotoxicity was schedule dependent; it was greatest when cells were exposed to DPM continuously during and following a 1-h exposure to DDP and less pronounced when DPM exposure was limited to pretreatment or concurrent treatment only. DPM increased DDP uptake in a concentration-dependent manner as measured with both [195mPt]-DDP and the DDP analogue [3H]-cis-dichloro(ethylenediamine) platinum. Nitrobenzylthioinosine, another nucleoside membrane transport inhibitor, did not enhance DDP cytotoxicity or uptake at concentrations that produced equivalent degrees of inhibition of [3H]uridine uptake. DPM did not interact synergistically through an increase in cellular cyclic AMP levels. DPM did not increase trypan blue or propidium iodide uptake, or change cell size, indicating that it did not nonspecifically increase membrane permeability. We conclude that DPM interacts synergistically with DDP and that, while an increase in DDP uptake is one component of the mechanism of this interaction, there are additional components since maximal effect was observed only with prolonged DDP exposure.
Carcinoma↗
Phase I trial of piroxicam in 62 dogs bearing naturally occurring tumors.
Piroxicam, a nonsteroidal antiinflammatory drug, was given to 62 dogs bearing naturally occurring tumors in a phase I clinical trial. Dose escalation was performed, with oral doses ranging from 0.5 mg/kg every 48 h (q48h) to 1.5 mg/kg q48h being tested. Dose-limiting gastrointestinal irritation/ulceration occurred in all four animals that received 1.5 mg/kg q48h. The maximum tolerated dose was 1 mg/kg q48h. Subclinical renal papillary necrosis occurred in two dogs (initial dosages, 1 and 1.5 mg/kg q48h, respectively). Following dose escalation, an additional group of dogs was treated with 0.3 mg/kg piroxicam q24h per os, the accepted canine dosage prior to this trial. Inclusion of this treatment group enabled evaluation of the toxicity of and tumor response to a daily dosage regimen. No complete remissions occurred in this trial. Partial remission was documented in three of ten dogs exhibiting transitional-cell carcinoma, in three of five animals bearing squamous-cell carcinoma, in one of three dogs displaying mammary adenocarcinoma, and in the one dog that exhibited a transmissible venereal tumor. The results of this study support the additional evaluation of piroxicam in a phase II clinical trial in dogs bearing naturally occurring tumors.
Animals↗
Mechanism-based model for tumor drug resistance.
The development of tumor resistance to cytotoxic agents has important implications in the treatment of cancer. If supported by experimental data, mathematical models of resistance can provide useful information on the underlying mechanisms and aid in the design of therapeutic regimens. We report on the development of a model of tumor-growth kinetics based on the assumption that the rates of cell growth in a tumor are normally distributed. We further assumed that the growth rate of each cell is proportional to its rate of total pyrimidine synthesis (de novo plus salvage). Using an ovarian carcinoma cell line (2008) and resistant variants selected for chronic exposure to a pyrimidine antimetabolite, N-phosphonacetyl-L-aspartate (PALA), we derived a simple and specific analytical form describing the growth curves generated in 72 h growth assays. The model assumes that the rate of de novo pyrimidine synthesis, denoted alpha, is shifted down by an amount proportional to the log10 PALA concentration and that cells whose rate of pyrimidine synthesis falls below a critical level, denoted alpha 0, can no longer grow. This is described by the equation: Probability (growth) = probability (alpha 0 less than alpha-constant x log10 [PALA]). This model predicts that when growth curves are plotted on probit paper, they will produce straight lines. This prediction is in agreement with the data we obtained for the 2008 cells. Another prediction of this model is that the same probit plots for the resistant variants should shift to the right in a parallel fashion. Probit plots of the dose-response data obtained for each resistant 2008 line following chronic exposure to PALA again confirmed this prediction. Correlation of the rightward shift of dose responses to uridine transport (r = 0.99) also suggests that salvage metabolism plays a key role in tumor-cell resistance to PALA. Furthermore, the slope of the regression lines enables the detection of synergy such as that observed between dipyridamole and PALA. Although the rate-normal model was used to study the rate of salvage metabolism in PALA resistance in the present study, it may be widely applicable to modeling of other resistance mechanisms such as gene amplification of target enzymes.
Animals↗
Antiviral nucleoside toxicity in canine bone marrow progenitor cells and its relationship to drug permeation.
The most promising nucleoside analogs that are currently undergoing preclinical and clinical testing for anti-HIV activity belong to the dideoxynucleoside group. We have studied the toxicity of 3'-azido,3'-deoxythymidine (AZT), 2',3'-dideoxycytidine (DDC), and 2',3'-dideoxyinosine (DDI) in canine bone marrow progenitor cells in culture. AZT potently inhibited both canine CFU-GM and CFU-E with IC50 values of 2 and 8 mumol/l respectively, while DDC was relatively non-toxic to either progenitor with IC50 of > 200 mumol/l and 80 mumol/l respectively. DDI was mildly toxic to the bone marrow progenitors, with IC50 values of 62 mumol/l for CFU-GM and 70 mumol/l for CFU-E. Dipyridamole, a nucleoside transport inhibitor, did not influence the toxicity of these dideoxynucleosides in either progenitor at concentrations up to 10 mumol/l. Using uridine as the prototype endogenous nucleoside, we have demonstrated that there is a saturable "zero-trans" nucleoside transport system in canine bone marrow mononuclear cells, which is completely inhibited by 1 mumol/l dipyridamole (Ki = 0.02 mumol/l). None of the dideoxynucleosides appeared to be a substrate for this transport system, and dipyridamole did not alter their influx. Permeation of radiolabeled AZT into bone marrow mononuclear cells was slow and non-saturable, while the permeation of DDI was even slower. DDC did not permeate bone marrow cells well, with very little cell accumulation even after 2 hours of equilibration. Our toxicity data from canine bone marrow progenitor cells paralleled the clinical hematotoxicity profiles of these dideoxynucleosides in AIDS patients and suggest that the myelotoxicity of a nucleoside analog is related to its ability to permeate the progenitor cells in question. Canine bone marrow progenitor cultures may serve well as an in vitro model for drug hematotoxicity studies.
Animals↗
Plasma and cerebrospinal fluid pharmacokinetics of cytosine arabinoside in dogs.
Cytosine arabinoside (ara-C) is a component of many protocols for the treatment of CNS (central nervous system) leukemia and lymphoma in humans and dogs. It is also used for the prophylaxis of CNS metastasis in acute lymphoblastic leukemia. Although ara-C enters the cerebrospinal fluid (CSF) of human cancer patients after i.v. administration, it is unclear whether a similar CNS distribution occurs in humans whose blood-brain barrier has not been compromised by invasive disease. No information on the penetration of ara-C into the CSF in dogs is available. We studied the plasma and CSF pharmacokinetics of 600 mg/m2 ara-C in ten healthy male dogs after its administration as a rapid i.v. bolus (six dogs) or as a 12-h i.v. infusion (four dogs). Ara-C concentration in blood and CSF samples was determined by high-performance liquid chromatography (HPLC). After an i.v. bolus of ara-C, the mean plasma distribution half-life was 7.1 +/- 4.5 min and the mean elimination half-life was 69 +/- 28 min. The mean plasma clearance was 227 +/- 125 ml min-1 m-2. The peak concentration of ara-C in the CSF was 29 +/- 11 microM, which occurred at 57 +/- 13 min after the ara-C bolus. The CSF elimination half-life was 113 +/- 26 min. During a 12-h infusion of ara-C (50 mg m-2 h-1), the plasma steady-state concentration was 14.1 +/- 4.2 microM, the CSF steady-state concentration was 8.3 +/- 1.1 microM, and the CSF: plasma ratio was 0.62 +/- 0.14. The plasma elimination half-life was 64 +/- 19 min and the plasma clearance was 214 +/- 69 ml min-1 m-2. The CSF elimination half-life was 165 +/- 28 min. No clinically significant toxicity was observed over a 21-day period following drug administration in either of the treatment groups. Our data indicate that ara-C crosses the blood-brain barrier in normal dogs and that i.v. administration of this drug has potential as a treatment modality for neoplasia involving the CNS.
Animals↗
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↗
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↗
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↗
Persistence and reactivation of Rickettsia tsutsugamushi infections in laboratory mice.
The persistence of R. tsutsugamushi in tissues of experimentally infected mice for 565 days was demonstrated. Reactivation of apparently dormant infections was accomplished by inoculating the mice with a heterologous strain of the organism or treatment with cyclophosphamide.
Animals↗
Patterns of rickettsemia and antibody response in silvered leaf monkeys (Presbytis cristatus) after inoculation with virulent and avirulent strains of Rickettsia tsutsugamushi.
Most silvered leaf monkeys inoculated with selected strains of Rickettsia tsutsugamushi developed rickettsemia. The time of onset and the duration of rickettsemia were related to the infecting strains, but these parameters could not be correlated with the virulence of the strain. The rickettsemia was not terminated by the appearance of humoral antibody, as detected by the indirect fluorescent antibody test. The specificities of the antibody responses were related to the antigens present in the infecting strains.
Animals↗
Virulence and antigenic properties of Rickettsia tsutsugamushi in a naturally infectei laboratory colony of Leptotrombidium (leptotrombidium) arenicola.
Over 1,200 isolations of R. tsutsugamushi were obtained over 7 generations of L. (L.) arenicola and no reproducible differences in virulence or antigenic markers could be detected among these isolations. The F8 generation yielded rickettsia with the same antigenic makeup and virulence properties as the original female parent mite. When these isolates were inoculated into mice they elicited the same predominant antibody specificities, i.e. they all produced antibody which reacted with the TA 763 and Karp strains. These were the same as the major antigens detected by direct fluorescent antibody staining of the isolates.
Animals↗
Clinical response of silvered leaf monkeys (Presbytis cristatus) to infection with strains of Rickettsia tsutsugamushi virulent and avirulent for mice.
Silvered leaf monkeys (Presbytis cristatus) inoculated with avirulent strains of Rickettsia tsutsugamushi showed little or no signs of disease, whereas those inoculated with moderately or fully virulent strains developed severe disease. Infection with the virulent strains produced early leukocytosis followed by leukopenia and significant decreases in packed-cell volumes. In animals infected with avirulent strains, these parameters were normal throughout the experimental period.
Animals↗