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Biomedical subjects

D H Ho

Publications and source records attributed to D H Ho.

117 records · Page 7Linked to original sources
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Peplomycin and bleomycin effects on human colon cancer cells.

The lethal effects of peplomycin and bleomycin on cultured human colon cancer cells (LoVo) were compared by using the technique of inhibition of colony formation. The survival of LoVo cells after treatment for 1 h with either peplomycin or bleomycin was characterized by a biphasic exponential curve. When the exposure time was extended to 24 h, both drugs produced much greater cytotoxic effects, with survival decreased to less than 0.10% for bleomycin and less than 0.02% for peplomycin. Both peplomycin and bleomycin, in a dose-dependent manner, inhibited the incorporation of thymidine into cells. On an equal-weight basis, the cytotoxicity of peplomycin (24-h exposure) was similar to that of bleomycin. Both agent also inhibited the incorporation of leucine and uridine after 24 h of drug exposure, but to a lesser extent than inhibition of thymidine incorporation. However, after 1 h of exposure, such inhibitory effects were minimal. These results demonstrate that prolonged peplomycin or bleomycin exposure produces greater cell-kill than shorter drug exposure. Schedules with continuous drug administration should be explored clinically.

Bleomycin↗
PubMedDate not supplied

Clinical pharmacology of polyethylene glycol-L-asparaginase.

Polyethylene glycol (PEG)-L-asparaginase, at doses ranging from 500 to 8000 units/m2, was infused iv over 60 min in 31 patients of whom 27 were evaluable pharmacokinetically. The plasma disappearance of PEG-L-asparaginase is described by a monophasic curve with a mean half-life of 357 +/- 243 hr which is much longer than that of the unconjugated enzyme (half-life of approximately 20 hr). The rate of total clearance (128 +/- 74 ml/m2 X day) is much slower than that of L-asparaginase (2196 +/- 1098 ml/m2 X day). The volume of distribution is 2093 +/- 643 ml/m2, which is similar to that of L-asparaginase, indicating that PEG-L-asparaginase is mainly localized in the plasma. No enzyme could be measured in urine samples taken from nine patients for a period of up to 4 days. Additionally, no enzyme was measurable in one patient's pleural fluid obtained at the end of infusion and 6 days after infusion of a 1000-unit/m2 dose; the corresponding concentrations in plasma were 0.64 and 0.62 units/ml, respectively. In general, the plasma enzyme concentrations at the end of the 1-hr infusion and at 14 days after drug administration were proportional to the dose given. However, in two patients, a sudden disappearance of enzyme levels occurred which preceded anaphylactic reactions during subsequent treatment. A third patient developed severe bronchospasm 30 min after the first dose, but his enzyme levels were within the normal range.

Adult↗
PubMedDate not supplied

Effects of cisplatin-induced nephrotoxicity on gentamicin pharmacokinetics in rats.

The effects of cisplatin-induced nephrotoxicity on the pharmacokinetics of a renally excreted antibiotic, gentamicin, were studied in F-344 rats. A single dose of gentamicin (30 mg/kg, iv) was given to different groups of rats alone, at the same time as, or on day 4, 7, 15, or 29 following cisplatin administration (6 mg/kg, iv). Cisplatin caused a significant decrease in gentamicin clearance and an elevation of gentamicin levels in plasma, kidneys, liver, and spleen at all the time points that were tested except concomitant administration. The maximum effect was seen when gentamicin was given on day 7 following cisplatin. The total clearance of gentamicin was reduced from 11 +/- 5 ml/(min X kg) in control rats to 2 +/- 2 ml/(min X kg) in cisplatin-treated rats. Twenty-four-hr urinary gentamicin excretion was decreased to 34 +/- 13% of the dose (control rats excreted 93 +/- 4% of dose). Rats given only gentamicin had a creatinine clearance of 5.9 +/- 0.6 ml/(min X kg), whereas those given gentamicin on day 7 following cisplatin had a creatinine clearance of 0.4 +/- 0.2 ml/(min X kg). Thus, cisplatin reduced gentamicin excretion in rats, resulting in elevated antibiotic levels in plasma and tissues for at least a month. Prior exposure to cisplatin may therefore be associated with an increased risk of toxicity from gentamicin, even when the antibiotic is administered in therapeutic doses. The effects of cisplatin on other renally excreted drugs need to be evaluated.

Animals↗
PubMedDate not supplied

Polyethylene glycol-L-asparaginase and L-asparaginase studies in rabbits.

Injections of polyethylene glycol (PEG)-L-asparaginase or L-asparaginase were given to two rabbits each at doses of 40 units/kg. Ten min following injection of either enzyme preparation, the plasma enzyme concentration was approximately 1 unit/ml. This level decreased steadily in the rabbits given L-asparaginase, with a t1/2 of approximately 20 hr. In contrast, the enzyme level in rabbits given PEG-L-asparaginase decreased much more slowly, with a t1/2 of approximately 144 hr. The slower disappearance rate of PEG-L-asparaginase resulted in greater values for the area under the concentration versus time curve and smaller values for total clearance. Immediately following the enzyme injections, no L-asparagine could be detected in the plasma, and a transient elevation of L-aspartic acid levels was noted. By 4 hr, the L-aspartic acid level in all of the rabbits returned to near normal. The L-asparagine, however, was not measurable as long as plasma enzyme was detectable. Levels of L-asparagine returned to normal 4 days after L-asparaginase administration, and 27 days elapsed before L-asparagine was detected in rabbits given PEG-L-asparaginase.

Amino Acids↗
PubMedDate not supplied

Distribution and inhibition of dihydrouracil dehydrogenase activities in human tissues using 5-fluorouracil as a substrate.

Dihydrouracil dehydrogenase activity, with 5-fluorouracil used as the substrate, was measured in human tissues and leukemic cells. The liver had the highest enzyme activity (mean, 705 nmoles/g tissue/hr) with minimal activity found in the kidneys, spleen, lung, colon, colon tumors, pancreas, breast tissue, breast tumors, bone marrow cells, and peripheral leukemic cells. Wide variations in the enzyme activities were noted in samples collected from different subjects. 5-diazouracil inhibits the enzyme activity with the concentration required for inhibiting 50% (IC50) of the liver enzyme being 3 microM. Other compounds, thymine, thymidine, 6-methoxydiazouracil, and cyclo-5-diazouridine were also tested for their effect on this enzyme. With the exception of cyclo-5-diazouridine, all others produced inhibitory effect. The inhibitory effect of 6-methoxydiazouracil is similar to that of diazouracil. Thymidine and thymine are less active with identical values for IC50 of 80 microM.

Dihydrouracil Dehydrogenase (NAD+)↗
PubMedDate not supplied

Correlation of mouse tissue distribution of arabinosylcytosine in vivo with enzymatic activities in vitro.

The distribution of arabinosylcytosine (ara-C) and its metabolites has been measured in the liver, small intestine, spleen, and kidney of mice inoculated ip 5-6 days earlier with L1210 leukemia cells. Two major metabolites were found in the tissues--the nucleotides and the deaminated inactive product, arabinosyluracil (ara-U). The decay curve of ara-C in most of these tissues was curvilinear; the ara-C half-lives estimated from the terminal phases were 8. 11, 12, and 12 hr for spleen, kidney, intestine, and liver tissues, respectively. The ara-C half-life was not correlated with the deoxycytidine deaminase activity in the tissues. However, the deaminase activity in vitro correlated well with the amount of ara-U present in vivo. Similar analyses were made for L1210 leukemic cells and ascites fluid. A high nucleotide level was found in the cells and a significant amount of nucleotides was also identifiable in the ascites fluid. The activities of deoxycytidine kinase, but not of deoxycytidine deaminase, in host tissues of mice inoculated with L1210 leukemic cells sensitive to ara-C were greater than in those of normal mice. The phosphorylating activities in vitro correlated with the amount of nucleotide present in vivo in mice bearing L1210 leukemic cells. However, the infiltration of leukemic cells containing high kinase activities into the host tissues accounted for most, if not all, of the nucleotide level in these tissues. This is further evidenced by the fact that inoculating mice with L1210 leukemic cells resistant to ara-C did not alter the kinase activity or nucleotide levels of the host tissues; these resistant cells contain negligible amounts of ara-C phosphorylating activities.

Aminohydrolases↗
PubMedDate not supplied

Distribution and inhibition of adenosine deaminase in tissues of man, rat, and mouse.

Adenosine deaminase activity, with arabinosyladenine (ara-A) used as the substrate, was measured in human leukemic cells and major tissues of man, rat, and mouse. The enzyme is stable in frozen tissues for at least 1 week, in frozen homogenate for several months, or after overnight dialysis at 4 degrees C in 0.25 M sucrose. The adenosine deaminase of chronic myelogenous leukemic (CML) cells has a Km of 0.6 mM and a Vmax of 183 mumols x 10(-2)/g of cells/minute. All species have highest activities in spleen and intestine. Kidney activity is highest in rat and lowest in man. The human brain has higher activity than the mouse or rat brain, and activity is higher in mouse liver than in human or rat liver. Activity in lung tissues is moderate and similar in all three species. The mean activity in CML cells is 195 mumols x 10(-2)/g of cells/minute, and the activity is higher in patients with CML in blast cell crisis. Acute myelogenous and lymphocytic leukemia cells also have very high activities. Drug concentrations required for inhibiting 50% of CML enzyme activity are 10 nM or erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), 0.6 nM of coformycin, and 0.3 nM of 2'-deoxycoformycin. Preincubation of the enzyme with coformycin, but not with EHNA, enhances the inhibition. In view of the high adenosine deaminase activities in tissues and the enhancement of the therapeutic effect of ara-A by inhibitors in mouse tumor systems, clinical trials of these combinations are warranted. They may be particularly beneficial to patients with CML in blast cell crisis.

Adenine↗
PubMedDate not supplied

Clinical pharmacology of 11-acetyl-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo (7.4.1.0(2,7).0(10,12) tetradeca-2,4,6-trien-6,9-diyl diacetate (FK 973).

FK 973, a novel substituted dihydrobenzoxazine structurally similar to mitomycin C, is a derivative of the product isolated from Streptomyces sandaensis. In vitro and in rodents, it is a potent antitumor agent. During Phase I clinical trials, we evaluated the pharmacologic properties of FK 973 in eight adenocarcinoma patients after a 30-min i.v. infusion of doses ranging from 7 to 45mg/m2. An established enzyme immunoassay that measures the stable deacetylated active metabolite FR66980 showed that the plasma drug levels declined biphasically with a terminal half life (t1/2 beta) of 4.7 +/- 1.6hr (mean +/- S.D.) The total clearance rate was 438 +/- 113ml/(min/m2). Both the maximum plasma drug concentrations (Cmax) and the area under the concentration-versus-time curve (AUC) were dose related. In addition to nausea and vomiting, alopecia, and myelosuppression, three patients experienced a delayed vascular-leak syndrome. The 3 patients had received doses among the highest studied, and the toxicity appeared to be dose related and cumulative. The evidence suggests that higher doses generated higher Cmax and AUC values, which may be correlated with toxic effects.

Acetylation↗