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T L Loo

Publications and source records attributed to T L Loo.

At least 73 records · Page 4Linked to original sources
PubMed1981

Stability and compatibility of antitumor agents in glass and plastic containers.

The stability of methotrexate, fluorouracil, cytarabine, dactinomycin, doxorubicin, bleomycin sulfate, mitomycin, mithramycin, vincristine sulfate, vinblastine sulfate, cyclophosphamide, dacarbazine, carmustine, and leucovorin calcium in underfilled plastic and glass administration containers was determined. Drugs were reconstituted according to manufacturers' instructions and added to 5% dextrose injection 50 ml in both polyvinyl chloride bags and glass partial-fill bottles. In addition, mitomycin was added to 0.9% sodium chloride injection 50 ml in both polyvinyl chloride bags and glass partial-fill bottles. All admixtures were stored at room temperature, not protected from light. Stability was determined over 24 hours (48 hours for doxorubicin and fluorouracil) by high-pressure liquid chromatography, except for cyclophosphamide (analyzed by mass spectrometry) and carmustine (analyzed by spectrophotometry). Methotrexate, leucovorin calcium, cytarabine, dactinomycin, mithramycin, vinblastine sulfate, cyclophosphamide, and dacarbazine were equally stable (10% or less change in concentration over 24 hours) in glass and plastic containers. Doxorubicin and fluorouracil were more stable in plastic containers than glass containers. The T90 value for doxorubicin in glass was 40 hours; there was no apparent decrease in plastic even after 48 hours. The T90 value for fluorouracil in glass was seven hours and in plastic, 43 hours. Vincristine sulfate, bleomycin sulfate, and carmustine were more stable in glass than plastic. The T90 value for vincristine sulfate in plastic was 10 hours. The T90 value for bleomycin sulfate in plastic was 0.7 hour. The T90 value for carmustine in plastic was 0.6 hour. Mitomycin dissolved in 0.9% sodium chloride injection was more stable in plastic. Mitomycin dissolved in 5% dextrose injection was not stable. Carmustine and bleomycin sulfate should be administered only in glass containers. Continuous infusions of doxorubicin and fluorouracil are more completely delivered from plastic containers. Mitomycin should not be dissolved in 5% dextrose injection.

Antineoplastic Agents↗
PubMed1981

Comparative structure-genotoxicity study of three aminoanthraquinone drugs and doxorubicin.

Two aminoanthraquinone analogs 1,4-bis(2-[(2-hydroxyethyl)amino]ethylamino)-9,10-anthracenedione (HAQ) and 1,4-dihydroxy-5,8-bis(2-[(2-hydroxyethyl)amino]ethylamino]-9,10-anthracenedione (DHAQ) have been shown to possess similar therapeutic activities against experimental tumors but different toxicities to the animals. In this study, the genotoxic effects of these two drugs and a new analog, 1,4-dihydroxy-5,8-bis(2-[(2-hydroxyethyl)amino]ethylamino]-9,10-anthracenedione diacetate, were analyzed by using mammalian cell cytogenetic assays (chromosome breakage and sister chromatid exchanges) as well as bacterial mutagenesis assays. The experimental therapeutic activities of these drugs in vivo correlated well with their in vitro genetic toxicities as revealed by cytogenetic assays; i.e., the drug with the highest therapeutic activity (DHAQ) was most active in inducing chromosome damage. DHAQ was also more genotoxic than Adriamycin. In cytogenetic assays, the activities of all drugs were reduced to different degrees in the presence of a S-9 metabolic system. Dis as revealed by cytogenetic assays; i.e., the drug with the highest therapeutic activity (DHAQ) was most active in inducing chromosome damage. DHAQ was also more genotoxic than Adriamycin. In cytogenetic assays, the activities of all drugs were reduced to different degrees in the presence of a S-9 metabolic system. Dis as revealed by cytogenetic assays; i.e., the drug with the highest therapeutic activity (DHAQ) was most active in inducing chromosome damage. DHAQ was also more genotoxic than Adriamycin. In cytogenetic assays, the activities of all drugs were reduced to different degrees in the presence of a S-9 metabolic system. Discrepancies were observed between results obtained from cytogenic assays and those from mutagenesis assays. Whereas DHAQ was most active in cytogenetic studies, Adriamycin was most mutagenic or toxic. HAQ was least active cytogenetically, and this activity was not changed appreciably in the presence of metabolic enzymes. However, it was metabolically activated to a bacterial mutagen. Our studies suggest that the cytogenetic and mutagenesis assays may be sensitive to the activities of different agents and of different moieties of the same agent. The application of short-term in vitro assays to identify the chemical structures responsible for genetic toxicity and for therapeutic activities in vivo may lead to the better understanding of drug activities and to the development of more effective drugs.

Animals↗
PubMed1981

Penetration of methylglyoxal bis(guanylhydrazone) into intracerebral tumors in humans.

Methylglyoxal bis(guanylhydrazone) (MGBG; NSC 32946) is currently being reevaluated for its clinical antineoplastic activity against both hematological and solid tumors. MGBG (100 to 200 mg/sq m) was administered by slow infusion over 3 hr to six patients during surgical resection of intracerebral tumors. Excised tumor tissue and plasma were assayed for MGBG by high-pressure liquid chromatography. In all cases, MGBG penetrated rapidly into brain tumor tissue. Viable tumor tissue contained greater concentrations of MBGB than did necrotic tumor tissue. In two patients with glioblastoma multiforme, MBGB concentrations in brain tumor tissue were five- to 19-fold higher than concurrent plasma samples. However, MGBG did not penetrate well into the cerebrospinal fluid of two patients with Ommaya reservoirs given i.v. MGBG (200 mg/sq m). The highest MGBG concentration in cerebrospinal fluid reached only 22% of the concurrent plasma levels. These studies suggest that MGBG may be a useful agent in the treatment of intracerebral tumors but may not be effective against meningeal leukemia and meningeal carcinomatosis.

Blood-Brain Barrier↗
PubMed1980

Treatment of cultured human colon carcinoma cells with fluorinated pyrimidines.

The shape of the initial part of the dose-dependent response curve of LoVo cells, an established human colon carcinoma cell line, exposed for 1 hr to graded concentrations of 5-FU depended on the medium supplement, i.e., fetal calf serum (FCS), in which the cells were treated and subsequently incubated for colony-formation. At concentrations of 50--100 micrograms/ml (equivalent to peak plasma levels following an in vivo bolus dose of 15 mg/kg) cell kill was completely prevented by FCS. The serum did not contain thymidine (TdR) but had significant amounts of uridine (UR). When 5-FU was delivered in dialyzed FCS, concentrations of 50--100 micrograms/ml achieved only a modest 15% cell kill after 1 hour treatment. Regardless of medium supplement, the killing effect of 5-FU did not increase beyond concentrations greater than 2,000 micrograms/ml. Increasing the exposure interval dramatically increased the killing of LoVo cells by 5-FU, although the effects of medium supplement on the degree of cell survival persisted for about 12 hours. Virtually all of the incorporated 5-FU was transformed into 5-FUR, and a very small proportion eventually was incorporated into nucleic acids, suggesting that the killing effect of 5-FU on LoVo cells is mediated mostly by ribosidation and not by conversion into the deoxyribonucleoside. This conclusion is supported by the failure of 5-FUdR to kill LoVo cells after a treatment interval of one hour, even at concentrations of 5000 micrograms/ml; yet after the same exposure interval, 5-FUR effectively killed cells at concentrations of 50--100 micrograms/ml. TdR afforded no protection from cell kill by 5-FU. In contrast, UR was capable of protecting LoVo cells from the lethal effects of both 5-FU and 5-FUR even at concentrations as low as 10 micrograms/ml. Ftorafur exposed to LoVo cells for 1 hour had a slight killing effect (about 20--25%) at concentrations ranging up to 2000 micrograms/ml. Although the lethal effect of ftorafur was slightly increased after longer periods of incubation, it failed to reach 90% even after intervals of 48 hours. The results on cellular sensitivity that we obtained for LoVo cells treated with various fluorinated pyrimidines differ substantially from those of other investigators who used different methods to assess cell killing on nonhuman and noncolonic cell systems. The predictive relevance of these data as compared to those obtained in other systems is justified by the suboptimal results with these agents in clinical practice.

Cell Line↗
PubMed1980

Pharmacological disposition of negatively charged phospholipid vesicles in rats.

The pharmacological disposition of four negatively charged phospholipid vesicles with radioactive cholesteryl oleate as a tracer was investigated in rats. The acidic phospholipids included phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, and diphosphatidylglycerol (cardiolipin). The blood half-life of phosphatidylserine vesicles was the shortest (< 2 min), while that of phosphatidylinositol was the longest (90 min). Cardiolipin and phosphatidylglycerol vesicles had intermediate blood half-lives (7 and 18 min, respectively). The distribution of these vesicles in six major organs (liver, spleen, heart, kidneys, lungs, and brain) varied greatly. Contrary to the long-held belief, it was possible to prepare negatively charged phospholipid vesicles with long blood half-lives. Furthermore, tissue disposition of these negatively charged vesicles could be manipulated partially by judicious selection of their components.

Animals↗
PubMed1980

The pharmacologic fate of the antitumor agent 2-amino-1,3,4-thiadiazole in the dog.

Anticipating the renewed clinical trial of the antitumor agent 2-amino-1,3,4-thiadiazole (AT, NSC-4728), we have studied the pharmacologic fate of AT-5-14C in beagle dogs. The drug was only minimally metabolized in 5 h; the radioactivities in the urine, and particularly in the plasma, resided almost entirely in unchanged AT. In four dogs, after IV administration of AT-5-14C at 10 mg/kg (200 mg/m2), 150-200 muCi per animal, the terminal plasma t1/2 of AT was 13 h, and less than 10% of the administered dose appeared in the urine in 5 h. When the dose was raised to 25 mg/kg (500 mg/m2) in four dogs, the average plasma t1/2 of AT was 10 h; the 5-h cumulative excretion of the agent was 9% of the dose in the urine, 0.3% in the bile, and 0.1% as 14CO2 in the expired air. The average total clearance of AT was 0.70 ml/kg/min. Drug concentrations in the cerebrospinal fluid were 95% of those in the plasma at semi-steady state. At autopsy 5 h after dosing, more than 75% of the administered radioactivity was retained in the body, the highest amounts in terms of micrograms per gram of wet tissue being in the liver, kidney, lung and stomach. No appreciable changes in AT pharmacokinetics were evident upon simultaneous IV administration of allopurinol at 30 or 60 mg/kg. AT was less than 7% bound to dog plasma protein at 25 degrees C in concentrations of 12-100 microgram/ml.

Animals↗
PubMed1980

Pharmacological disposition of N-(phosphonacetyl)-L-aspartate in humans.

The pharmacological disposition of N-(phosphonacetyl)-L-aspartate (PALA), an antitumor transition state analog currently in clinical trial, has been studied in 19 patients after i.v. administration of the agent at doses ranging from 800 to 5000 mg/sq m; PALA in biological specimens was assayed enzymatically, advantage being taken of its inhibition of L-aspartate carbamoyltransferase (EC 2.1.3.2) PALA disappeared from plasma biexponentially, with an average terminal t 1/2 of 5.3 hr. It was excreted in the urine unchanged; the 24-hr cumulative excretion was 85% of the administered dose. The average total clearance was 1.60 ml/kg/min and was linearly related to creatinine clearance, suggesting that in humans PALA is essentially cleared by glomerular filtration. The apparent volume of distribution of PALA was 309 ml/kg, approximately the sulfate space in humans. PALA penetrated into the central nervous system only to a limited extent. Tumor L-aspartate carbamoyltransferase activity was also measured before and 1.5 hr to 6 days after PALA administration; in all eight studies, a notable decrease in enzyme activity was observed.

Aspartate Carbamoyltransferase↗
PubMed1980

Pharmacological disposition of 1,4-bis (2-[(2-hydroxyethyl)amino]-ethylamino)-9,10-anthracenedione diacetate in the dog.

1,4-Bis (2-[(2-hydroxyethyl)amino]ethylamino)-9,10-anthracenedione (NSC 287513) (HAQ) may be selected for clinical trial based on its activity against a number of transplantable rodent tumors. Using a high-pressure liquid chromatograph assay, we have studied the pharmacological fate of HAQ in beagles. After i.v. administration of HAQ at 15 mg/kg (300 mg/sq m), the initial plasma t1/2 of the agent was 9.4 min, and the terminal t1/2 was 115.2 min. A maximal plasma concentration of 24.9 mg of HAQ per liter was attained. A high plasma clearance of 23.5 ml/kg/min was observed in these animals. The extrapolated apparent volume of distribution was 693.7 ml/kg, comparable to that of antipyrine in the dog. In 5 hr, 24.0% of the administered HAQ has been excreted in the urine unchanged, and a trace of a metabolite was detected, amounting to less than 2% of the UV-absorbing (254 nm) materials. However, hepatobiliary excretion constituted the primary route of drug elimination since 39.5% of the dose was found in the bile during the same period. An extraction procedure has been developed to quantify HAQ in tissue homogenates with 75 to 80% recovery. At autopsy, 5 hr after dosing, drug distribution in terms of percentage of the dose administered is as follows: liver, 7%; kidneys, 3.5%; pancreas, 3.1%; small intestine, 1.5%; stomach, 1.3%; spleen, 0.7%; lungs, 0.5%; heart, 0.4%; large intestine, 0.4%; and brain, 0.2%.

Animals↗
PubMed1980

Penetration of N-(phosphonacetyl)-L-aspartate into human central nervous system and intracerebral tumor.

Cerebrospinal fluid (CSF) was obtained from five patients by lumbar puncture and from two patients by Ommaya reservoir tap after the i.v. administration of the antitumor agent N-(phosphonacetyl)-L-aspartate (PALA). PALA was quantified enzymatically by inhibition of the target enzyme, aspartate carbamoyltransferase. After a 1-hr infusion of PALA, its CSF concentration steadily rose until the eighth hr, at which time it was 12 to 40% of concurrent plasma concentration. PALA concentration then declined more gradually in CSF than in plasma, and CSF concentrations exceeded plasma concentrations by 24 hr. PALA concentration X time product in CSF was 12 to 25% of that in plasma. PALA was infused i.v. for 30 to 60 min into eight patients undergoing surgical resection if intracerebral tumors. Its concentration in intracerebral tumor was greater than or comparable to concentration in temporalis muscle in four of six patients from whom muscle was obtained. The PALA concentration in edematous brain tissue was consistently lower than the concentration in tumor or muscle. In a patient undergoing occipital lobectomy, the PALA concentration in brain was inversely proportional to the distance from the tumor. PALA reached concentrations in intracerebral tumor that appeared to be similar to concentrations reported previously in s.c. tumors, although biopsy techniques and conditions differed.

Aspartic Acid↗
PubMed1979

Kinetics of gallium nitrate, a new anticancer agent.

Pharmacokinetic studies were conducted in 8 patients with disseminated neoplasms refractory to conventional chemotherapy, who received gallium nitrate at doses of 300 to 600 mg/m2 intravenously in a phase I clinical trial. Gallium concentrations in biological fluids were determined colorimetrically. In patients with normal renal function, gallium showed a biphasic plasma disappearance with an initial half-life (t1/2) of 0.5 to 1.8 hr (mean 1.0) and a terminal t1/2 of 10.5 to 50.4 hr (mean 25.1). Gallium was distributed in total body water and often localized in some body compartment as evidenced by a volume of distribution ranging from 0.25 to 2.53 L/kg (mean 1.19). The total drug clearance from the plasma was 0.13 to 1.00 ml/kg/min (mean 0.65) in patients with normal renal function. Cumulative urinary excretion of gallium was 15% to 72% (mean 35%) of the administered dose in 24 hr (it fell to 23% in 8 days in a patient with acute oliguric renal failure). Gallium kinetics are altered in patients with acute renal dysfunction and in patients who have received multiple doses of gallium or other metal chemotherapy.

Adult↗
PubMed1979

Dichloroallyl lawsone.

Dichloroallyl lawsone (DCL, NSC-126771), a synthetic analogue of the antimalarial lapachol, is potentially useful in cancer chemotherapy. Unlike most anticancer agents, DCL is not significantly myelosuppressive in animals but it induces acute cardiac toxicity in the rhesus monkey. This cardiac toxicity seems to be correlated with the maximal plasma DCL concentration, about 130 mg/L in the monkey. We have studied DCL pharmacokinetics in patients in an attempt to define safe dose limits for the Phase I clinical trial. After the rapid intravenous infusion of 10 mg/m2 of radioactive [1- or 4-14C]DCL, 250 muCi per patient, the mean peak plasma concentration of unchanged DCL in four patients was 2.9 +/- 0.3 mg/L. The drug had a mean initial plasma half-life of 48.9 +/- 19 min and a terminal half-life of 20.3 +/- 1.8 hr, with a C X t of 50.1 +/- 12 mg/L/hr, and a clearance rate of 0.08 ml/kg/min. These data suggest that in clinical trials the DCL dose given by rapid intravenous infusion should not exceed 450 mg/m2 so that the maximal plasma drug concentration remains below 130 mg/L.

Antineoplastic Agents↗
PubMed1979

Synthesis and biological activities of ftorafur metabolites. 3'- and 4'-hydroxyftorafur.

Four isomers of ftorafur were synthesized as authentic samples of possible ftorafur (FT) metabolites. 2,3-Dihydrofuran was treated with perbenzoic acid in MeOH to give 2-methoxy-3-hydroxytetrahydrofuran, which upon treatment with Ac2O/pyridine yielded the key intermediate 2-methoxy-3-acetoxytetrahydrofuran. The other intermediate, 2-ethoxy-4-acetoxytetrahydrofuran, was prepared by acid hydrolysis (HCl/50% EtOH) of 1,1-diethoxy-3,4-dihydroxybutane, followed by acetylation (Ac2O/pyridine). Treatment of 2,4-bis(trimethylsilyl)-5-fluorouracil with either 2-methoxy-3-acetoxytetrahydrofuran or 2-ethoxy-4-acetoxytetrahydrofuran in 1,2-dichloroethane at room temperature using SnCl4 as catalyst afforded cis- and trans-3'-OAc-FT or 4'-OAc-FT, respectively. However, trans-3'-OAc-FT and cis-4'-OAc-FT were the major condensation products. In each case, separation of these cis and trans isomers was achieved by silica gel column chromatography. Treatment of 3'- or 4'-OAc-FT with NH3/CH3OH at 5 degrees C overnight yielded the described hydroxylated FT. Both trans-3'-OH-FT and cis-4'-OH-FT showed no significant activity against L1210 up to 100 mg/kg. These two agents produced an inhibitory effect on HeLa cell growth equal to that of ftorafur, with ID50 = 200 MICROGRAMS/KG.

Animals↗
PubMed1979

Clinical pharmacology of intravenously administered trimethoprim-sulfamethoxazole.

Pharmacokinetic studies of intravenously administered trimethoprim-sulfamethoxazole (TMP-SMX) were conducted in 11 patients with cancer while they received therapy with this drug combination for infection. Each patient received 160 mg of TMP and 800 mg of SMX every 8 h. The highest plasma concentrations of both agents were attained at the end of a 1-h infusion period, and the levels were maintained above 38 mug of free SMX and 2 mug of TMP per ml for 2 to 4 h on day 1. On day 4, these concentrations were exceeded at all time intervals of blood sampling. High concentrations of TMP and free SMX were recovered in the urine during the 8-h period. The plasma half-lives of TMP and free SMX, as determined during the first 8-h period, were 7.6 and 8.6 h, respectively. Compared with SMX, TMP had an approximately 2.5 times higher volume of distribution. This drug combination was well tolerated by the patients and unaccompanied by drug-related toxicity.

Adolescent↗
PubMed1979

High-pressure liquid chromatographic analysis of 3-deazauridine-5'-triphosphate in human cancer cells.

A rapid high-pressure liquid chromatographic assay for the detection and quantitation of 3-deazauridine-5'-triphosphate (deazaUTP), the active metabolite of the anticancer drug 3-deazauridine (deazaUrd), in cell extracts is described. This procedure permits the simultaneous detection and quantitation of CTP, the cellular concentration of which is affected by treatment with deazaUrd. Human lymphoblastoid cells (line CCRF-CEM) treated with 100 nmols of deazaUrd/ml in culture accumulate deazaUTP to greater than 25 nmols/10(7) cells after 4 hours. The concentration of CTP in these cells decreased exponentially with a half-life of 1.1 hours. After these cells had been incubated with 100 nmols of deazaUrd/ml and were resuspended in drug-free medium, the intracellular deazaUTP concentration decreased exponentially with a half-life of 3.4 hours. This assay has been applied to clinical studies of deazaUrd; high cellular deazaUTP concentrations have been detected in brain tumor tissue after deazaUrd infusion.

3-Deazauridine↗
PubMed1979

Human urinary metabolites of 1-(tetrahydro-2-furanyl)-5-fluorouracil (ftoraful).

Two hydroxylated metabolites were isolated from the urine of a patient who had received ftorafur (5 g/sq m). These metabolites were identified by mass spectrometry and nuclear magnetic resonance spectroscopy as trans-3'- and cis-4'-hydroxyftorafur. The compounds were not converted to 4-fluorouracil when incubated in plasma, base (pH 9), or water. Because of their stability, it is unlikely that these metabolites are in vivo precursors of 5-fluorouracil. There are indications that less stable, unisolatable, hydroxylated ftorafur derivatives are intermediates in the conversion of ftorafur to 5-fluorouracil.

Chemical Phenomena↗