Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several biochemical parameters were examined relative to the sensitivity or resistance of representative rodent tumors to N-(phosphonacetyl)-L-aspartate (PALA). The activity of the target enzyme, L-aspartate transcarbamylase (ATCase), was evaluated in homogenates of a spectrum of murine neoplasms. ATCase activity was significantly lower in PALA-sensitive as opposed to PALA-refractory tumors. However, among tumors sensitive to PALA, there was no clearcut relationship between ATCase activity and degree of sensitivity to PALA. Thus, a number of hypotheses were proposed to explain differential sensitivity to PALA in vivo. Enzyme activities in the salvage pathway which phosphorylate pyrimidine nucleosides and deoxynucleosides were found to be greater in refractory tumors. The uptake of PALA, in vitro, though quite slow, was found to be two to eight times greater in two sensitive tumors as compared to the refractory L1210 leukemia. However, in vivo, 24 hours following graduated doses of PALA, nearly identical intratumoral drug concentrations were observed in representative sensitive and refractory tumors. Thus, ultimately, PALA transport would not appear to correlate with differences in drug sensitivity. A number of other biochemical parameters were also found to have no association with sensitivity to PALA in vivo. These included: kinetics of inhibition of ATCase, capacity for restitution of ATCase activity after a dose of PALA, degree of inhibition of ATCase at various doses of PALA, detoxification of PALA by tumor cells, kinetics of uptake of uridine, or catabolism of pyrimidines or pyrimidine nucleosides.
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PMID:Mechanisms of sensitivity or resistance of murine tumors to N-(phosphonacetyl)-L-aspartate (PALA). 47 6

N-(Phosphonacetyl)-L-aspartate (PALA) is an analog of the transition state for the aspartate transcarbamylase reaction and has been reported previously to be a potent and specific inhibitor of de novo pyrimidine nucleotide biosynthesis. It is now shown that PALA has considerable antitumor activity against certain transplantable tumors in mice. PALA, unlike other antimetabolites, was less effective against ascitic leukemias than against two solid tumors, B16 melanoma and Lewis lung carcinoma. Another solid tumor, Ridgway osteogenic sarcoma, which is sensitivie to many established chemotherapeutic agents, did not respond to PALA. Daily or intermittent treatment with PALA did not significantly increase the life-span of mice bearing i.p. leukemia L1210. The survival time of mice bearing i.p. P388 leukemia was prolonged by PALA treatment by up to 64%. In a number of experiments mice bearing i.p. B16 melanoma survived 77 to 86% longer than did controls when treated with PALA (490 mg/kg) on Days 1, 5, and 9. Lewis lung carcinoma, a tumor refractory to most established antineoplastic agents, was highly sensitive to PALA. Treatment on Days 1, 5, and 9 following s.c. implantation of Lewis lung carcinoma was curative to 50% of the mice. If treatment was delayed until s.c. Lewis lung tumors had reached about 500 mg, PALA neither cured the mice nor produced significant tumor regression. However, extensive delay of tumor growth and prolongation of survival were still observed.
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PMID:Antitumor activity of N-(phosphonacetyl)-L-aspartic acid, a transition-state inhibitor of aspartate transcarbamylase. 106 66

The sugar boronated thymidine nucleoside, 5' -0-[(triphenylphosphine-boryl) carbonyl]-3'-0-acetyl thymidine 1, and the boron-modified nucleoside phosphotriester, 5'-(diethylphosphite- cyanoborane)-3'-acetylthymidine 2, were successfully synthesized. Both compounds demonstrated differential activity when tested against eight cell lines, with significant cytotoxic activity against the growth of human Tmolt3 leukemia, colon adenocarcinoma, HeLa S3 uterine carcinoma, and osteosarcoma cells. In in vivo studies these agents were found to be active against the growth of Ehrlich ascites carcinoma at 8 mg/kg/day I.P. and to be marginally active against the growth of L1210 and Lewis lung cancers in mice. The mode of action of these thymidine derivatives in Tmolt3 cells was the inhibition of DNA and protein synthesis. Compound 2 was highly effective in inhibiting DNA polymerase alpha and m-RNA, r-RNA and t-RNA polymerase activities. Both compounds inhibited ribonucleoside reductase activity. The de novo purine pathway appeared to be the major site of inhibition of the agents, with IMP dehydrogenase, PRPP amido transferase, and dihydrofolate reductase activities being significantly inhibited. In the pyrimidine pathway, carbamyl phosphate synthetase and aspartate transcarbamylase activities were inhibited by 1. As expected, d[NTP] levels were significantly reduced by treatment with the agents. DNA strand scission was evident after incubating Tmolt3 cells for 24 hr with the agents.
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PMID:Antineoplastic activity of boron-containing thymidine nucleosides in Tmolt3 leukemic cells. 150 1

This article reports a Phase I study of combined therapy with N-(phosphonacetyl)-L-aspartate (PALA) and L-alanosine in 26 patients with advanced cancer. Each agent exhibits antitumor effect by enzyme inhibition: PALA blocks pyrimidine biosynthesis by impeding aspartate transcarbamylase and L-alanosine depletes purine nucleotides by interfering with adenylosuccinate synthetase. These agents were selected for clinical investigation in light of synergistic cytotoxicity in vitro against human tumor cell lines and in vivo against P-388 murine leukemia resistant to cytosine arabinoside. Dose-limiting toxicities were stomatitis and diarrhea to a lesser extent. There was no substantial myelosuppression. The authors recommend either of two intravenous regimens for studies of therapeutic activity in selected patients with neoplastic diseases: a one-day treatment repeated of PALA, 5.0 g/m2 and L-alanosine, 3.0 g/m2, repeated every 3 weeks; or a monthly program of PALA, 500 mg/m2/d 1-5 and L-alanosine, 60 mg/m2/d 1-5.
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PMID:A Phase I study of the combination N-(phosphonacetyl)-L-aspartate (PALA, NSC-224131) and L-alanosine (NSC-153353) in patients with advanced cancer. 686 Oct 99

Two murine cell lines, L1210 leukemia (T-cell) and B16 melanoma, and 3 human cell lines, CCRF-CEM leukemia (T-cell), NC37 lymphoblasts (B-cell) and IPC-48 melanoma were compared with respect to sensitivity to N-(phosphonacetyl)-L-aspartate (PALA), growth rate and aspartate transcarbamylase activity. No correlation between drug sensitivity and growth rate was found. The melanoma cell lines were more sensitive to PALA than were the lymphocytic cell lines. The 2 T-cell leukemia lines had similar sensitivities to PALA while the B-lymphoblasts were more resistant at 10(-3) M PALA and less resistant at 10(-4) M PALA than were L1210 and CCRF-CEM cells. Aspartate transcarbamylase activity was similar among the 2 melanoma cell lines and among the 3 lymphocytic cell lines and was 2-fold higher in the latter.
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PMID:Inhibition of cell growth by N-(phosphonacetyl)-L-aspartate in human and murine cells in vitro. 727 1

N-Substituted indan-1.3-diones have proven to be potent cytotoxic agents effective against the growth of single cell leukemia tumors and cell lines derived from solid tumors. A number of the derivatives were active against growth of solid tumors e.g. colon, lung bronchogenic and osteosarcoma for which few effective agents are available to inhibit their growth. These agents inhibited DNA and RNA synthesis of L1210 cells. The de novo purine synthetic pathway was inhibited at PRPP amido transferase and IMP dehydrogenase. The pyrimidine synthetic pathway was inhibited at aspartate transcarbamylase. Other sites which demonstrate minor inhibition were DNA polymerase alpha, r- and t-RNA polymerase, ribonucleoside reductase, dihydrofolate reductase, nucleoside kinases and thymidylate synthetase. In addition d(NTP) pool levels were reduced by the drugs. L1210 DNA strand scission was evident after exposure to drugs for 24 hr. at 100 microM.
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PMID:Cytotoxicity and mode of action of substituted indan-1, 3-diones in murine and human tissue cultured cells. 784 49

In this paper, we describe a short synthesis of N-(phosphonoacetyl)-L-aspartate (PALA) analogues. The mono- and difluorinated thioacetamide precursors were prepared in one step from methyl (diethoxyphosphono)di- and monofluoromethyldithioacetates 8 and 11 as starting materials. Antiproliferating properties on a L1210 strain and ATCase inhibition of these new compounds are disclosed. ThioPALA(FF) 5c showed a remarkable cytotoxic activity towards murine leukemia L1210, when used as tetraester.
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PMID:Efficient synthesis of fluorothiosparfosic acid analogues with potential antitumoral activity. 1597