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Biomedical subjects

T L Loo

Publications and source records attributed to T L Loo.

At least 91 records · Page 5Linked to original sources
PubMed1979

Enzymatic assay for the antitumor agent-N-(phosphonacetyl)-L-aspartic acid (PALA).

A method is described for the assay of N-(phosphonacetyl)-L-aspartic acid in plasma or urine, based on inhibition of partially purified aspartate carbamoyltransferase from rat liver. Concentrations of N-(phosphonacetyl)-L-aspartic acid as low as 0.1 microgram/ml can be detected. Plasma disappearance and urinary excretion curves from one patient are shown as examples of the application of the method.

Animals↗
PubMed1979

Cell cycle phase-specific cytotoxicity of the antitumor agent maytansine.

The objective of this investigation was to study the effects of maytansine on the cell cycle kinetics of HeLa cells. The results of this study indicate that maytansine is a very potent mitotic inhibitor and that it has no effect on macromolecular synthesis. Maytansine-induced cytotoxicity was dependent upon the position of the cell in the cell cycle. Mitotic and G2 cells are most sensitive to this agent, while G1 phase cells are the most resistant, with S-phase cells being intermediate. Small (0.82 X 10(-8) M) fractionated doses given at an interval of 8 hr have been found to be more cytotoxic than was a large (1.63 X 10(-8) M) single dose. In evaluating the drug combinations, we observed that the schedule in which 1-beta-D-arabinofuranosylcytosine treatment was followed by maytansine treatment exhibited greater cell kill than the reverse sequence. No schedule-dependent effects were observed when maytansine was tried in combination with Adriamycin.

Cell Cycle↗
PubMed1979

Penetration of 3-deazauridine into human brain, intracerebral tumor, and cerebrospinal fluid.

The antitumor agent 3-deazauridine (DAU) was administered rapidly to four patients before surgical removal of intracerebral tumor. Tumor, adjacent brain tissue, and temporalis muscle were assayed for DAU by high-pressure liquid chromatography. DAU penetrated comparably into tumor, brain, and muscle; in one patient, tissue concentrations were higher than concurrent plasma concentrations. The active metabolite 3-deazauridine 5'-triphosphate was quantitated in one tumor sample and greatly exceeded its Ki for cytidine 5'-triphosphate synthetase. DAU was also present in autopsy brain specimens from two patients treated shortly antemortem. Cerebrospinal fluid concentrations were 22.1 and 59.0%, respectively, of concurrent plasma concentrations during continuous infusion of DAU in two patients. Cerebrospinal fluid concentration was 3.1 microgram/ml 2 hr after a 30-min infusion of 1.5 g of drug per sq m and fell to 1.9 microgram/ml at 16 hr. Thus, DAU is capable of penetrating into intracerebral tumor, brain, and cerebrospinal fluid and is worthy of investigation in the treatment of intracerebral and meningeal neoplasms.

3-Deazauridine↗
PubMed1979

Pharmacokinetics and disposition of 3-deazauridine in humans.

3-Deazauridine (3-DAU) pharmacology was studied in 20 patients who received the drug by rapid or continuous infusion. In 8 studies, the plasma clearance of 3-DAU after rapid administration was biphasic, with an average terminal t1/2 of 4.4 hr and an extrapolated volume of distribution of 0.57 liter/kg. After 5-day continuous infusion of 3-DAU, the plasma clearance was also biphasic, with an average terminal t1/2 of 21.3 hr and an extrapolated volume of distribution of 18.8 liter/kg. 2,4-Dihydroxypyridine, the aglycone of 3-DAU, was observed in plasma but not in urine of patients receiving the drug by rapid infusion. The urinary excretion of 3-DAU was low, only 7.8% 24 hr after rapid infusion and 7.2% up to 4 days after continuous infusion. Tissue distribution of 3-DAU was determined from autopsy samples of 2 patients. Not only were high levels of 3-DAU detected in the tissues studied, but 3-DAU triphosphate, the active metabolite of 3-DAU, was present in brain, lung, and liver.

3-Deazauridine↗
PubMed1978

Clinical, toxicological, and pharmacological studies of combination chemotherapy of adenocarcinoma with adriamycin and Baker's antifolate.

Ten patients with disseminated adenocarcinoma were treated with combination chemotherapy employing Adriamycin and Baker's Antifolate (BAF). There were seven patients with lung adenocarcinoma, two of whom achieved partial remission while the remaining five had their disease stabilized. Drug toxicity to the bone marrow, gastrointestinal mucosa, and skin was dose-limiting and was greater than the known toxicities of the individual drugs. Pharmacological studies of both drugs were performed on five patients to determine whether abnormal pharmacokinetics could explain this collateral toxicity. Adriamycin plasma concentrations and disappearance seemed to be unaffected by BAF. However, BAF levels were prolonged, apparently due to an Adriamycin effect on the plasma elimination of BAF, resulting in a prolonged exposure of sensitive tissues and organs to BAF. Consequently, when BAF and Adriamycin are used in combination, appropriate dose and schedule changes must be made to avoid any potentially serious side effects.

Adenocarcinoma↗
PubMed1978

Synthesis and antitumor activity of halogen-substituted 4-(3,3-dimethyl-1-triazeno)quinolines.

Halogenated 4-(3,3-dimethyl-1-triazeno)quinolines were synthesized as potential antitumor agents on the basis of the biochemical pharmacological properties of existing triazenes, their structural-activity relationships, and the high melanin binding of chloroquine and iodoquine in vivo and in vitro. They were synthesized by diazotization of appropriate halogen-substituted 4-aminoquinolines in fluoboric acid at -5 degrees C followed by coupling with dimethylamine. Among these new compounds, 8-chloro-4-(3,3-dimethyl-1-triazeno)quinoline produces significant antitumor activity against both P-388 and L1210 murine leukemias. Although only marginally active or inactive against P-388, the other chloro, bromo, or iodo analogues show activity against L1210 comparable to that of dacarbazine (DIC). However, none of these compounds is active against B-16 melanoma. Compared with DIC these new agents demonstrate a higher in vitro affinity for melanin; however, this affinity is apparently not correlated with their antitumor activity.

Animals↗
PubMed1978

Clinical pharmacology of systemic chemotherapeutic agents in skin neoplasms.

Considerable progress recently has been made in the systemic chemotherapy of disseminated skin neoplasms. Several agents are particularly useful in this regard: the nitrosoureas, methotrexate, actinomycin D, and dacarbazine. This paper reviews their pharmacologic disposition in man. The nitrosoureas have short plasma half-lives; however, they are extensively degraded to metabolites that persist in the body, and are only slowly excreted. Highly soluble in lipids, the nitrosoureas penetrate significantly into the central nervous system. Actinomycin D is only minimally metabolized in vivo; its elimination from the plasma shows a prolonged slow phase with a half-life of 36 hours; but its excretion is even slower than expected about 30% in a week. A potent inhibitor of dihydrofolate reductase, methotrexate exhibits a multiphasic plasma disappearance, and accumulates in tissues with high dihydrofolate reductase activities. At the normal therapeutic dosages, methotrexate is eliminated by the kidneys as the unchanged drug; appropriate dosage modifications are mandatory if renal function is compromised. Dacarbazine has a relatively short plasma half-life, and is rapidly excreted partly as the unchanged drug; it undergoes extensive biotransformation in the body. Like other antitumor agents, these drugs may cause gastrointestinal toxicities and myelosuppression; in addition each drug can have its own individual organ toxicity.

Antineoplastic Agents↗
PubMed1978

Disposition and metabolism of 1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur) in humans.

The pharmacology of high-dose 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT) has been studied by radiochemical and chromatographic techniques in eight patients. Plasma disappearance of FT was exponential, with a half-life of 8.8 hr. Plasma concentrations of 5-fluorouracil (FUra) were sustained at 12.8 nmol/ml (1.7 microgram/ml) for at least 48 hr after FT administration. The concentrations of FUra derived from the administration of FT were considerably greater than were those achieved by constant infusion of FUra at the maximal tolerated dose of 1.1 g/sq m without causing unacceptable mucositis. The cumulative urinary excretion was 20% of the administered dose in 24 hr. FT underwent in vivo biotransformation to 2 hydroxytetrahydrofuranyl-5-fluorouracil derivatives in addition to anabolites and catabolites of FUra. High concentrations of FT and FUra were present in the cerebrospinal fluid, which could account for the severe central nervous system toxicity of FT at high doses. We conclude that the antitumor activity of FT is partially attributable to its slow release of FUra.

Animals↗
PubMed1977

Cellular response to treatment with 4-(3-(2-chloroethyl)-3-nitrosoureido)-cis-cyclohexanecarboxylic acid, a water-soluble nitrosourea derivative.

The lethal effects of 4-(3-(2-chloroethyl)-3-nitrosoureido)-cis-cyclohexanecarboxylic acid (cis-acid), a water-soluble nitrosourea derivative, were investigated on a human lymphoma cell line. The survival of asynchronous cells exposed to increasing concentrations of the drug was characterized by a threshold exponential curve (Do = 20 microgram/ml; Dq = 20 microgram/ml, 1 hour) similar to that of other nitrosourea derivatives. cis-Acid exerted its main killing effect on cells in early S and in late G2 phase. Cells in mid S and early G1 phase were tenfold more resistant. Changes in survival response as a function of cell cycle stage were reflected primarily by changes in the extent of the shoulder region of the survival curve. In contrast to other nitrosoureas, the lethal effectiveness of cis-acid in solution was stable and the drug could sterilize large numbers of cells in short periods of time. Another important major difference observed for cis-acid with respect to classic nitrosourea derivatives was the capacity of treated cells to recover from sublethal and potentially lethal damage. Our studies have shown that cis-acid is as effective in killing cultured human lymphoma cells as other nitrosoureas, but possibly with a mechanism different from that of these compounds. The major shortcoming noted for cis-acid, namely the capacity of treated cells to recover from drug-induced damage, is offset by the relatively long stability of its killing effect. This, and the fact that cis-acid can be administered in an aqueous solution, make this agent an appealing compound for clinical trials.

Antineoplastic Agents↗
PubMed1976

Uptake of 1-beta-D-arabinofuranosylcytosine and prednisolone by synchronized human lymphoma cells.

The cytotoxicity of many antitumor agents exhibits cell-cycle phase specificity. Using a human lymphoma cell line synchronized by thymidine block, we have investigated the differential uptake of radioactive 1-beta-D-arabinofuranosylcytosine (ara-C) and prednisolone in various phases of the cycle. Uptake of ara-C is highest during early S and declines steadily throughout the rest of the cycle. In comparison, prednisolone demonstrates no significant age-dependent difference in uptake although its cytotoxicity is cell cycle sensitive.

Cell Division↗
PubMed1976

Combination chemotherapy in vitro with cis-dichlorodiammineplatinum(II).

Cis-dichlorodiammineplatinum(II) (DDP) was paired with 11 other chemotherapeutic drugs in a search for possible synergistic pairs. Cell lethality was investigated by the colony-formation technique utilizing a long-term culture of human lymphoma cells. Synergistic effects were noted for pair combinations with all alkylating agents, bleomycin, adriamycin, camptothecin, and cytosine arabinoside. Additive effects were recorded for combinations with prednisolone and VP-16-213, while DDP reduced the capacity of cells to absorb sublethal damage induced by alkylating agents.

Alkylating Agents↗