Inhibition of DNA polymerase alpha by bleomycin.
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Bleomycin↗
Biomedical subjects
M M Wick
Publications and source records attributed to M M Wick.
Inhibition of reverse transcriptase by tyrosinase generated quinones related to levodopa and dopamine.
Several derivatives of levodopa have been shown to be potent inhibitors of the sulfhydryl enzyme, RNA dependent DNA polymerase, reverse transcriptase (RT). In the presence of the polyphenol oxidase, tyrosinase, the inhibitory values were between 10(-6) M and 10(-5) M. Structure-activity studies revealed that active oxidation or reduction was necessary for this potent inhibitory response. Spectrophotometric analysis showed that the presence of both the quinone and quinol was required for maximum inhibitory activity. These data suggest that the common intermediate of oxidation of quinols or reduction of quinones (i.e., semiquinone) is the active species. The use of tyrosinase provides a convenient model for the detection of the actual inhibitory interaction of a free-radical (semiquinone) with a biologically important macromolecule, reverse transcriptase.
Avian Myeloblastosis Virus↗
Inhibition of clonogenic growth of melanoma cells by combination of melanocyte stimulating hormone and theophylline.
The combination of MSH and theophylline is synergistic in inhibiting the growth as well as stimulating the differentiation of pigmented melanoma cells. In order to determine if a permanent alteration in the proliferative potential of these cells was achieved, we examined the effect of MSH and theophylline alone and in combination upon the plating efficiency and tumorigenicity of S-91 Cloudman melanoma cells. Following treatment with the combination of MSH and theophylline, the cells became deeply pigmented and had their colony forming ability reduced to 28% of control. Neither MSH or theophylline alone, although effective in reducing the growth rate of the cells, caused a significant reduction in clonogenic growth. When cells were pretreated with MSH and theophylline alone or in combination and reinjected into mice, the combination of MSH and theophylline caused a significant reduction in percentage of animals developing tumor (reduced to 14% of control). Cells treated with either MSH or theophylline alone were similar in their tumorigenic potential to control cells. These effects were selective since the nonmelanocytic control cells, mouse fibroblast L929 and Chinese hamster ovary when treated similarly did not exhibit any alteration in their clonogenic potential. The treatment of responsive cells with the combination of MSH and theophylline is capable of causing permanent decrease in the proliferative potential of murine melanoma cells and may have relevance to the treatment of this disease in man.
Animals↗
Synthesis and biologic evaluation of the dopamine analog N-acetyldopamine in experimental leukemia in mice.
N-Acetyldopamine is a relatively nontoxic analog of dopamine that has shown significant antitumor activity in experimental L1210 and P388 leukemias. A convenient two-step chemical synthesis of this derivative provided a sufficient quantity of material to study the effects of the administration of this drug by a more frequent schedule. The antitumor activity in the L1210 and P388 systems was significantly improved when N-acetyldopamine was administered to (C57BL/6J x DBA/2)F1 (B6D2F1) mice three times daily for 4 days. Long-term survivors appeared, which indicated tumor kills in excess of 10(5) cells. The effects of dopamine and N-acetyldopamine on the incorporation of radioactively labeled thymidine (dThd) by proliferating tissues (tumor, bone marrow, and gastrointestinal mucosa) were examined in tumor-bearing B6D2F1 mice. The dThd incorporation into tumor cells was selectively inhibited in both the L1210 and P388 leukemias with less inhibition of bone marrow and gastrointestinal mucosa cells. One hour after a dose of 400 mg N-acetyldopamine/kg, dThd incorporation was completely suppressed by both P388 and L1210 tumor cells with minimal effects on bone marrow or gastrointestinal mucosa cells. The synthetic method reported here is applicable to the preparation of various derivatives for study.
Animals↗
Clinical characteristics of early cutaneous melanoma.
Clinical characteristics of the primary tumor in 786 patients with superficial spreading melanoma were studied in a prospective sequential series of patients from the Melanoma Clinical Cooperative Group. The most useful features for early diagnosis were change in size and change in color, present in 71% and 55% respectively of patients with level II lesions. Increase in height of lesion correlated with more advanced disease. Ulceration and bleeding were predominantly found in advanced primary lesions and are consequently of limited use in early recognition. Awareness of the historical and clinical features of the primary tumor should result in early recognition and cure of most primary superficial spreading melanomas.
Adult↗
An experimental approach to the chemotherapy of melanoma.
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Antineoplastic Agents↗
Antitumor effects of L-glutamic acid dihydroxyanilides against experimental melanoma.
L-glutamic acid, gamma-(p-hydroxyanilide), is a naturally occurring metabolic inhibitor found in mushrooms and shown to be active against B-16 melanoma in vivo. We have prepared and evaluated 2 analogs, the 3,4- and 2,5-dihydroxy derivatives, since these might represent more immediate precursors to the putative biologically active quinone. Both dihydroxy derivatives were more toxic than the parent phenol. The 2,5-dihydroxy derivative was significantly more cytotoxic with a 5-fold decrease in IC50 for both human and B-16 melanoma cells in vitro. In the presence of mushroom tyrosinase, both derivatives were potent inhibitors of isolated DNA polymerase with essentially complete inhibition occurring at concentrations of 10(-5) M. The 3,4-dihydroxy derivative exerted inhibitory effects primarily upon thymidine incorporation into melanoma cells in vitro while the 2,5-dihydroxy derivative also inhibited uridine and leucine incorporation. There was no significant antitumor activity observed in the B-16 system, a fact which might be attributed to the increased toxicity of the compounds.
Anilides↗
Natural resistance to methotrexate in human melanomas.
Human melanomas are naturally resistant to methotrexate (MTX). The mechanism of intrinsic drug resistance has been explored in 3 melanoma cell lines not previously exposed to this agent. All 3 lines exhibited relative MTX resistance with ID50 values of greater than 1 microM. Drug uptake studies were performed over an extracellular concentration range of 0.1 to 10 microM MTX. The uptake was linear over the initial 10 min at all concentrations and subsequently reached plateau levels only at the 10 microM concentration. Lineweaver-Burke transformations yielded apparent Km (uptake) values of 1.4 to 5 microM, similar to data obtained from other human cell lines. The level of dihydrofolate reductase (DHFR) in the human melanoma cells ranged between 8.42 to 11.98 pmoles/mg protein. The melanoma DHFR levels are several fold higher than in MTX-sensitive human tumor lines and up to a hundred-fold higher than that measured in human brain tumor cells by our assay. The intrinsic resistance of these melanoma lines has therefore been attributed to elevated intracellular levels of DHFR.
Drug Resistance↗
Levodopa and dopamine analogs as DNA polymerase inhibitors and antitumor agents in human melanoma.
Levodopa and dopamine are naturally occurring catecholamines with antitumor activity in several experimental tumor systems. Previous studies suggested that their cytotoxic effect was related in part to their inhibitory effect upon DNA polymerase. We have examined the effects of levodopa, dopamine, levodopa methyl ester, norepinephrine, and the analog 3,4-dihydroxybenzylamine upon human and murine melanoma cells. When exponentially growing cells were exposed to these drugs, a characteristic inhibition of thymidine incorporation was observed with much less inhibition of either uridine or leucine incorporation. In order to ascertain that inhibition was occurring at the level of DNA synthesis, we examined the effects of the drugs upon the incorporation of thymidine triphosphate by permeabilized melanoma cells. When melanoma cells were permeabilized by lysolecithin, thereby permitting the direct incorporation of labeled thymidine triphosphate, a similar inhibition of incorporation was observed. Dopamine at a concentration of 4.8 microM caused a 50% reduction in incorporation of label. These results suggested that inhibition did occur at the level of DNA synthesis. In the presence of the melanocyte-specific oxidase, tyrosinase, these derivatives are potent inhibitors of isolated DNA polymerase alpha with 50% inhibitory concentrations between 1 and 10 microM. The inhibition could be completely prevented by the presence of reducing agents such as dithiothreitol (1.0 mM). The quinols themselves were not inhibitors of DNA polymerase. Dopamine analogs represent an interesting class of antitumor agents with inhibitory activity for DNA polymerase.
Animals↗
Structural analogues of L-glutamic Acid gamma-(4-hydroxyanilide) and gamma-(3,4-dihydroxyanilde) as potential agents against melanoma.
Nine heretofore unknown mono- and dihydroxyanilide analogues of the cytotoxic mushroom metabolites L-glutamic acid gamma-(4-hydroxyanilide) (1) and L-glutamic acid gamma-(3,4-dihydroxyanilide) (3, agaridoxin) were synthesized and tested as inhibitors of the growth of B16 mouse melanoma cells in culture. The naturally occurring anilides 1 and 3 had ID50 values of 0.10 and 0.27 mM, respectively. The analogue of 1 in which the gamma-L-glutamyl moiety was replaced by beta-L-aspartyl showed only a threefold decrease in activity, whereas attachment of the phenolic OH group to the meta instead of the para position resulted in a tenfold decrease. Other structural modifications, such as O-methylation or deletion of the carboxyl or amino group in the side chain, led to compounds of still lower activity (ID50 greater than 1.0 mM). The only analogue in the series with more activity than either 1 or 3 against B16 cells was L-glutamic acid gamma-(2,5-dihydroxyanilide) (14), which had an ID50 value of 0.051 mM. These data suggest that the gamma-L-glutamyl side chain in 1 or 3 plays a significant role in the biological action of these compounds, though some flexibility appears to exist insofar as the positioning of OH groups on the aromatic ring is concerned.
Anilides↗
Selective toxicity of 6-hydroxydopa for melanoma cells.
The growth inhibitory effect of 6-hydroxydopa, a cytotoxic analog of L-dopa, was studied in melanotic and amelanotic Cloudman melanoma, mouse fibroblast L929 and Chinese hamster ovary cells. A marked sensitivity of pigmented cells to 6-hydroxydopa was observed with a 10-fold increase in sensitivity of pigmented cells. Sensitivity correlated with the capacity of cells to incorporate radiolabeled exogenous L-dopa. The drug affected primarily DNA and RNA synthesis with greater inhibition observed in pigmented cells than the nonpigmented control cells. The mechanism of action may involve interaction with the melanocyte specific enzyme, tyrosinase, as a false substrate.
Animals↗
3,4-Dihydroxybenzylamine: a dopamine analog with enhanced antitumor activity against B16 melanoma.
3,4-Dihydroxybenzylamine (DHBA), a dopamine analog, was much less toxic than dopamine when tested against the B16 melanoma in vivo and in vitro. Daily doses of 1,000 mg DHBA/kg were better tolerated than doses of 400 mg dopamine/kg. When tested against the B16 melanoma in (C57BL/6 x DBA/2)F1 mice, DHBA had a significantly improved therapeutic effect as shown by a life-span increased 70% as compared to 48% with dopamine. DHBA shared the catecholamine property of selectively inhibiting thymidine incorporation as compared to leucine or uridine incorporation. Because the inhibitory effects of DHBA on the B16 melanoma cells in vitro were similar to those of dopamine, much of the improved efficacy in vivo might be attributed to decreased toxicity.
Animals↗
Levodopa and dopamine analogs: melanin precursors as antitumor agents in experimental human and murine leukemia.
L-Dopa methyl ester has been shown to be a novel antitumor agent. Furthermore, the L-dopa analogs, D-dopa, alpha-methyldopa, and dopamine, also exhibit significant antitumor activity in the L1210 and P388 lymphocytic leukemia systems. Structure-activity studies confirmed that the presence of a catechol moiety was essential for activity. Two analogs, 3,4-dihydroxybenzylamine and N-acetyldopamine, which were much less neurotoxic, exhibited the greatest antitumor activity. In vitro, at concentrations from 0.5 to 3.0 mM, there is a rapid and profound inhibition of radiolabeled thymidine incorporation as compared to uridine or leucine incorporation. Continuous exposure of exponentor up to 24 hours resulted in a block of traverse of cells through the cell cycle in G1 coupled with a depletion of cells with a G2 complement of DNA. In vivo, toxicity of these compounds appears to be mediated principally by conversion to dopamine. Similar effects upon thymidine incorporation were observed in human leukemia cells in vitro.
Animals↗
Levodopa therapy and malignant melanoma.
Concern has been voiced over a role for levodopa in the induction or stimulation of growth of cutaneous malignant melanoma. Prospective query of 1,099 patients of the Melanoma Clinical Cooperative Group at the time of presentation of their primary melanoma showed only one patient who had been taking levodopa. It was concluded that levodopa, if a factor in the induction of melanoma, must be playing an inconsequential role in the rapid rise in incidence observed for this tumor over the past decade.
Adult↗
L-Dopa methyl ester: prolongation of survival of neuroblastoma-bearing mice after treatment.
L-Dopa has has been shown to demonstrate enhanced toxicity toward melanoma cells in vitro. Since melanocytes arise from the neural crest embryologically, the effect of L-dopa methyl ester, a soluble analog, on the murine C1300 neuroblastoma was studied. There was significant antitumor activity against the neuroblastoma, which was enhanced by combination with a dopa decarboxylase inhibitor, Ro4-4602. In vitro studies suggested inhibition of DNA synthesis as the principal site of action. A mechanism involving sulfhydryl compound scavenging is postulated.
Animals↗
Enhancement of L-dopa incorporation into melanoma by dopa decarboxylase inhibition.
Melanoma cells possess a special biochemical pathway for the conversion of L-dopa to melanin. Selective incorparation of exogenous L-dopa into melanoma cells in vivo has been limited by extensive decarboxylation to dopamine. Pretreatment of animals bearing the S-91 Cloudman or ACI melanomas with Ro4-4602, a potent dopa decarboxylase inhibitor limited incorporation of label into adrenal tissue and enhanced entry of label into tumor. Six hours following pretreatment, the ratio of tumor to adrenal specific activities was altered from 0.25 to 1.5 for the S-91 melanoma and 0.68 to 1.99 for the ACI melanoma indicating diversion of metabolism away from catecholamine formation. The possibility of a selective diagnostic and/or therapeutic approach is proposed.
Adrenal Medulla↗
Dopamine: a novel antitumor agent active against B-16 melanoma in vivo.
L-dopa methyl ester has been shown to be an effective antitumor agent against the B-16 melanoma in vivo. We have now examined the analog, dopamine, a major catabolite of L-dopa. Dopamine administration at a daily dose of 600 mg/kg resulted in a 48% (p less than .001) increase in survival of treated mice as compared to non-treated controls. In vitro, an effect similar to that observed with L-dopa methyl ester was noted, specifically, a rapid and profound inhibition of thymidine incorporation with little effect on uridine or leucine incorporation. We have postulated that the inhibition of a DNA polymerase might be the site of action of these novel antitumor agents.
Animals↗
l-Dopa methyl ester as a new antitumour agent.
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Animals↗