Biomedical subjects

I H Hall

Publications and source records attributed to I H Hall.

267 records · Page 15Linked to original sources

PubMedDate not supplied

The cytotoxicity of [(N-alkyl-1,3-dioxo-1H,3H-isoindolin-5-yl)oxy]-alkanoic acids in murine and human tissue cultured cell lines.

Substituted isoindoline-1,3-diones are effective cytotoxic agents, causing cell death in a number of tissue culture lines, e.g. L1210, Tmolt-3, and HeLa-S3. In general these agents were not active against the solid cell growth, i.e. KB, skin, colon, HCT-8 ileum, colon, bronchogenic lung, osteosarcoma and glioma. The mode of action of the derivatives involves inhibition of de novo purine synthesis of Tmolt-3 cells, which reduces DNA and RNA syntheses. Purine synthesis was reduced by compound 4 at both regulatory enzymes, i.e. PRPP amido transferase and IMP dehydrogenase. The agent lowered d(GTP) pools, further reducing DNA synthesis. DNA strand scission was evident after incubation with Compound 4 for 24 hr at 100 microM, lowering DNA synthesis and causing cell death.

Amidophosphoribosyltransferase↗

PubMedDate not supplied

The cytotoxic activity of 1-acyl- and 1,2-diacyl-4,4-diethyl-3,5-pyrazolidinediones.

The 1-acyl- and 1,2-diacyl-4,4-diethyl-3,5-pyrazolinediones proved to be cytotoxic against the growth of a number of cell lines, including murine and human leukemias. HeLa suspended carcinoma, colon adencarcinoma SW480, KB nasopharynx and glioma tumors. Selected compounds were also active in the human lung bronchogenic MB-9812, and osteosarcoma TE418 screens. These derivatives were active in vivo in the Ehrlich ascites carcinoma screen in CF-1 mice at 8 mg/kg/day I.P. The mode of action in Tmol3 leukemia cells showed that the compounds reduced de novo synthesis of purines and pyrimidines and inhibited dihydrofolate reductase and ribonucleoside reductase activities. The DNA molecule was not a target although limited DNA strand scission may be possible.

Adenocarcinoma↗

PubMedDate not supplied

Cytotoxicity and mode of action of substituted indan-1, 3-diones in murine and human tissue cultured cells.

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.

Adenocarcinoma↗

PubMedDate not supplied

Cytotoxicity of ribo-and arabinoside boron nucleosides in tissue culture cells.

Ribose and arabinoside boron nucleoside derivatives were shown to be potent cytotoxic agents in murine and human suspended and solid tumor cell lines. The arabinoside derivative inhibited DNA and RNA synthesis with the protein synthesis requiring a higher concentration of drug for inhibition within 60 min. The purine pathway appeared to be the major target of the arabinoside 1 with inhibition of PRPP amido transferase and IMP dehydrogenase activities. Blockage of this pathway afforded reductions of deoxyadenosine and deoxyguanosine nucleotide pools. The DNA template did not appear to be target of the arabinoside 1, in that there was no change in DNA viscosity, thermal denaturation or absorption of nucleosides of DNA. However, compound 1 when incubated with L-1210 cells for 24 hr. showed a slight shift of the DNA in the gradient and moderate inhibition of ct-DNA topoisomerase II was demonstrated by 1 in vitro.

Animals↗

PubMedDate not supplied

Antineoplastic activities of alpha-, beta-, and gamma-alkylaminopropiophenone derivatives in mice and in murine and human tissue culture cells.

A number of alpha-, beta-, and gamma-alkylaminopropiophenone derivatives were found to be potent antineoplastic agents in CF(I) mice by inhibiting the growth of Ehrlich ascites carcinoma at 8 mg/kg/day and in vitro cytotoxic agents against murine and human cancer cell growth. Two analogs, beta-dimethylaminopropiophenone (1) and beta-pyrrolidinopropiophenone (3), were further tested for their in vitro effects on the metabolism of Tmolt3 cells. beta-Dimethylaminopropiophenone demonstrated potent reduction of DNA synthesis, RNA synthesis, and the pool levels of the dNTPs. Enzyme activities, such as DNA polymerase a, ribonucleotide reductase, PRPP amidotransferase, and most significantly, dihydrofolate reductase, were reduced by the agents from 25 to 100 microM after 60 min.

Animals↗

PubMedDate not supplied

Antineoplastic activities of alpha-methyl-beta-alkylaminopropiophenone derivatives in tissue culture cells.

A series of a-methyl-beta-alkylaminopropiophenone derivatives demonstrated potent antineoplastic effects. In CF1 mice, three compounds showed over 70% inhibition against the Ehrlich ascites carcinoma growth. In tissue culture cells, most of these agents demonstrated potent cytotoxicity in suppressing the growth of a number of murine and human cancer cell lines. In the mode of action studies in Tmolt-3 cells, alpha-methyl-beta-hexamethyleneiminopropiophenone (#14) was observed to reduce DNA synthesis significantly at 25 microM within 60 minutes incubation. The site of action of this agent appears to involve the reduction of purine de novo synthesis and IMP dehydrogenase activity. But significant inhibition of dihydrofolate reductase activity and DNA strand scission was noted.

Animals↗

PubMedDate not supplied

Boron substituted deoxyribonucleosides as cytotoxic agents.

Base substituted boronated nucleosides and phosphate modified nucleotides were examined for their cytotoxic activity in both murine and human tissue cultured cancer cells. These derivatives demonstrated better activity against the growth of single cell suspensions than solid cell tumor cell growth. A detailed mode of action study showed that 2'deoxyriboadenosine-N7-cyanoborane 6 suppressed Tmolt3 DNA synthesis preferentially with the major target of the agent being the purine de novo pathway. The activities of one of the regulatory enzymes of the pathway were reduced by the agents, i.e. PRPP-amido transferase. Other sites in the cell which were moderately affected by the agent were nucleoside kinase activities. DNA polymerase alpha and dihydrofolate reductase activities. The DNA molecule itself did not appear to be a target of the compound.

Animals↗

PubMedDate not supplied

The cytotoxicity of adenosine 5'-[N,N-di-(gamma-o-carboranyl)propyl] phosphorodiamidate in human Tmolt3 leukemic cells.

Adenosine 5'[N,N-di-(gamma-o-carboranyl)propyl] phosphorodiamidate 1 was successfully synthesized and characterized. The compound demonstrated potent in vivo antineoplastic activity and in vitro cytotoxicity in murine and human leukemia and uterine carcinoma tumor cell lines. In human T cell leukemia DNA preferentially was inhibited with key enzymes in the purine pathway being effectively inhibited by the agent. Marginal inhibition of the activities DNA polymerase a, carbamyl phosphate synthetase, nucleoside kinases, and thymidylate synthetase was observed. Tmolt3 DNA strand scission was observed after 24 hr. incubation with compound I at 100 microM.

Adenosine↗

PubMedDate not supplied

The cytotoxicity of 1-(phenylmethyl)-4,7,10-tris-[(4'methylphenyl) sulfonyl]-1,4,7,10-tetraazacyclododecane in human Tmolt3 T leukemic cells.

1-(phenylmethyl)-4,7,10-tris-[(4'methylphenyl)-sulfonyl]-1,4,7, 10-tetraazacyclododecane proved to possess potent in vivo antineoplastic and in vitro cytotoxicity in murine and human tissue cultured cells. In Tmolt3 leukemic cells 1-(phenylmethyl)-4,7,10-tris-[(4'methylphenyl)sulfonyl]-1,4,7, 10-tetraazacyclododecane inhibited the activities of the regulatory enzymes of the purine pathway leading to significant reductions in both RNA and DNA synthesis. Other sites of action of the compound which led to reductions of nucleic acid synthesis were suppression of nucleoside kinase and thymidylate synthetase activities and reductions in the d[NTP] pool levels. DNA fragmentation occurred which should be linked directly with cancer cell death.

Antineoplastic Agents↗

PubMedDate not supplied

Cytotoxicity of copper complexes of 2-furaldehyde oxime derivatives in murine and human tissue cultured cell lines.

The copper complexes of furan oxime derivatives were found to be potent cytotoxic agents in both murine and human tissue cultured cell lines which were either suspended or solid tumors. The ED50 values were frequently improved over the clinically useful antineoplastic agents. These copper complexes of 2-furaldehyde oximes were effective inhibitors of L1210 lymphoid leukemia DNA synthesis followed by RNA synthesis. Purine synthesis regulatory enzyme activities were markedly reduced by the compounds with marginal inhibition of t-RNA polymerase, and nucleoside kinases activities. L1210 DNA topoisomerase II activity was markedly reduced with IC50 values better than the standard VP-16, etoposide. Yet, the copper complexes caused no further protein linked breaks than VP-16 did, but did block phosphorylation activation of the topoisomerase II enzyme.

Animals↗

PubMedDate not supplied

Synthesis and antitumor activity of boronated dipeptides containing aromatic amino acids.

N-[(Trimethylamine-boryl-carbonyl]-L-tryptophan methyl ester and N[(trimethylamine-boryl)-carbonyl]-L-histidine methyl ester were obtained by synthesis using triphenyl-phosphine/carbon tetrachloride or dicyclohexyl-carbodiimide as coupling agents, respectively. Both agents reduced L1210 lymphoid leukemia DNA, RNA, and protein syntheses with the largest reductions occurring in DNA synthesis. Reductions in DNA synthesis appear to be mediated by inhibition of key enzyme activities (i.e., DNA polymerase a, IMP dehydrogenase, and PRPP amido transferase). These agents had little effect on in vitro L1210 DNA topoisomerase II activity at 100 microM but were able to cause synergistic increases in protein-linked DNA breaks when combined with etoposide (VP16). It was shown that these agents significantly reduced protein kinase C mediated phosphorylation of human topoisomerase II in vitro. Thus, inhibition of topoisomerase II phosphorylation may be a mechanism by which these agents and VP-16 are synergistic in causing protein-linked DNA breaks.

Animals↗

PubMedDate not supplied

Cytotoxicity of ferratricarbadecaboranyl complexes in murine and human tissue cultured cell lines.

The ferratricarbadecaboranyl salts [1-(eta 5-C5H5)Fe-2-CH3-2,3,4-C3B7H9] + X-(X- = AsF6-, 1 and SbF6-, 2), as well as the neutral complex, 1-(eta 5-C5H5)Fe-2-CH3-2,3,4-C3B7H9, 4, are effective cytotoxic agents, causing cell death in a number of tissue culture lines, e.g. L-1210, Tmolt3, HL-60, and HeLa-S3. In general, these agents were not active against the solid cell growth, i.e. KB nasopharynx, A431 skin, HCT-8 ileum, SW480 colon, osteosarcoma, and glioma. However, they were active against the growth of lung bronchogenic MB-9812. The mode of action of the derivatives involves inhibition of de novo purine synthesis of L-1210 cells, which reduces DNA and RNA syntheses. Purine synthesis was reduced by complexes [1-(eta 5-C5H5)Fe-2-CH3-2,3,4-C3B7H9]+ [SbF6]- 2 and ¿[1-(eta 5-C5H5)Fe-2-CH3-2,3,4-C3B7H9]+ [SbF6]- [1-(eta 5-C5H5)Fe-4-CH3-2,3,4-C3B7H9]+ [SbF6]-¿ [20:1] 3, at the regulatory enzyme, i.e. PRPP amido transferase. The agents lowered d[ATP] and d[CTP] pools, further reducing DNA synthesis. The salts 1, 2, and 3 were shown to be moderate inhibitors of isolated L-1210 DNA topoisomerase activity. DNA strand scission was evident after incubation with compounds 1-4 and [1-(eta 5-C5H5)Fe-2-CH3-2,3,4-C3B7H9 and 1-(eta 5-C5H5)Fe-4-CH3-2,3,4-C3B7H9] [20:1] 5, for 24 hours at 100 microM, lowering DNA synthesis, and causing cell death. The ferratricarbadecaboranes show activities and specificities different than those found for the analogous ferrocenium salts [(eta 5-C5H5)2Fe]+ [AsF6]- 6 and [(eta 5-C5H5)2Fe]+ [SbF6]- 7, and the neutral ferrocene compound (eta 5-C5H5)2Fe 8. The bioactivites of both the tricarbaboranyl and metallocenium salts are attributed to the cations, since Na+[AsF6]- 9, K+ [AsF6]- 10, Na+[SbF6]- 11, and K+[SbF6]- 12 were found to be inactive at equivalent ionic concentration.

Animals↗

PubMedDate not supplied

Effect of plasma TNF-alpha on filgrastim-stimulated hematopoiesis in mice and humans.

STUDY OBJECTIVE: To delineate possible explanations for a nonmonotone hematopoiesis, dose-response curve with filgrastim therapy after high-dose chemotherapy DESIGN: Sequential two-phase study. SETTINGS: University teaching hospital and basic pharmaceutical sciences laboratory. SUBJECTS: Thirty-nine patients with breast cancer or melanoma and 15 normal CF-1 male mice. INTERVENTIONS: Serial blood samples were obtained from patients after high-dose chemotherapy to evaluate hematopoiesis and tumor necrosis factor-alpha (TNF-alpha) concentrations. Murine hematopoiesis was induced by filgrastim with or without coadministration of lipopolysaccharide. MEASUREMENTS AND MAIN RESULTS: Detection of plasma TNF-alpha in patients corresponded to substantially slower recovery of granulocytes, erythrocytes, and platelets, and was directly proportional to the prescribed dosage of filgrastim. Lipopolysaccharide stimulated the secretion of TNF-alpha in mice and totally aberrated filgrastim-induced granulopoiesis. CONCLUSIONS: This in vivo evidence suggests that regulatory pathways involving endogenous cytokines may override the effect of recombinant cytokines.

Adult↗

PubMedDate not supplied

Substituted carboranes and polyhedral hydroborate salts as anti-neoplastics.

Substituted carboranes and polyhedral hydroborate salts were observed to be potent anti-neoplastic/cytotoxic agents inhibiting the growth of mouse and human leukemias, human uterine, colon adenocarcinoma, lung bronchogenic and gliomas. Amino-o-carborane-hydrochloride 7, one of the more potent compounds, preferentially inhibited Tmolt3 DNA synthesis. The target of the agent appears to be de novo purine synthesis with significant inhibition of the activities of both regulatory enzymes, PRPP-amido transferase and inosine monophosphate dehydrogenase as well as dihydrofolate reductase. The agent also inhibited nucleoside kinase activities leading to reductions in deoxyribonucleotide pools. The DNA molecule itself was not a target of the agent.

Adenocarcinoma↗

PubMedDate not supplied

The cytotoxicity of copper(II) complexes of 2-acetyl-pyridyl-4N-substituted thiosemicarbazones.

A series of 2-acetyl-pyridyl-4N-substituted thiosemicarbazones copper(II) complexes was evaluated for their cytotoxic mode of action in a variety of human and rodent tumor cell cultures. It was determined that these compounds may induce cytotoxicity by affecting several metabolic pathways including a reduction in de novo purine synthesis, and inhibition of IMP dehydrogenase, and DNA polymerase alpha activities. Selected compounds also demonstrated the ability to inhibit L1210 DNA topoisomerase II activity at micromolar concentrations. These agents were able to antagonize etoposide-induced formation of cleavable complexes as measured by K+/SDS precipitation and in vitro cleavage reactions.

Animals↗