Synergistic interaction between 1-beta-D-arabinofuranosylcytosine, thymidine, and hydroxyurea against human B cells and leukemic blasts in vitro.

Streifel, Jerome A.; Howell, Stephen B.

doi:10.1073/pnas.78.8.5132

Cited by 27 publications

(14 citation statements)

References 37 publications

(34 reference statements)

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“…The inhibitors of DNA synthesis used in this study effectively depressed the rate of DNA synthesis and histone synthesis but did not inhibit the rate of total protein synthesis (Table 1 (41). Cytosine arabinoside is a competitive inhibitor of deoxycytidine and is a chain terminator when it is incorporated into DNA in place of deoxycytidine (14).…”

Section: Resultsmentioning

confidence: 99%

Interrelationships of protein and DNA syntheses during replication of mammalian cells.

Sariban¹,

Wu²,

Erickson³

et al. 1985

Mol. Cell. Biol.

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During the replication of chromatin, the syntheses of the histone protein and DNA components are closely coordinated but not totally linked. The interrelationships of total protein synthesis, histone protein synthesis, DNA synthesis, and mRNA levels have been investigated in Chinese hamster ovary cells subjekted to several different types of inhibitors in several different tefiporal combinations. The results from these studies and results reported elsewhere can be brought together into a consistent framework which combines the idea of autoregulation of histone biosynthesis as originaly proposed by W. B. Butler and G. C. Mueller (Biochim. Biophys. Acta 294:481-496, 1973] with the presence of basal histone synthesis and the effects of protein synthesis on L)NA synthesis. The proposed framework obviates the difficulties of Butler and Mueller's model and may have wider application in understanding the control of cell growth.Most histone synthesis in eucaryotic cells occurs coordinated with DNA synthesis during the S-phase period of the cell cycle and is inhibited when DNA synthesis is inhibited (27, 32); however, an appreciable amount of histone synthesis has been found to occur in the G1 portion of the cell cycle and the Go state when there is no DNA replication (49, 51, 52). Butler and Mueller (8) showed that the coordination between histone and DNA synthesis resulted from alterations in the level of histone mRNA. The level of translatable histone mRNA in exponentially growing cells was greatly decreased when they were treated with inhibitors of DNA synthesis, and this in turn resulted in the inhibition of histone protein synthesis. However, when total protein synthesis was inhibited by cycloheximide or puromycin at the same time that DNA synthesis was inhibited with hydroxyurea, translatable histone mRNA levels did not decrease. Subsequently, investigators in several laboratories, measuring the levels of histone mRNAs by using cloned histone genes (5,12,17,20,21,30,38,39,42,43), have substantiated and extended those results to show that the histone mRNA is rapidly degraded during the inhibition of DNA synthesis but protected from degradation when protein synthesis is also inhibited.To explain their own results, Butler and Mueller (8) proposed a model in which the histone not bound to chromatin inhibited the translation of its own mRNAs, and presented evidence that the level of free histone in the cytoplasm did increase after treatment of cells with hydroxyurea. Others have also found evidence for a small but measurable pool (25).The general idea of autoregulation of histone synthesis has persisted (17,40,43) DNA synthesis from histone mRNA levels. They proposed that a protein with a short half-life coupled the two processes; thus, it rapidly disappeared when protein synthesis was iphibited. Alternatively, Graves and Marzluff (17) proposed that changes in deoxynucleotide metabolism may be involved in the regulation of histone mRNA levels.All these reports have concentrated on studies of histone mkNA levels and ...

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Section: Resultsmentioning

confidence: 99%

Interrelationships of protein and DNA syntheses during replication of mammalian cells.

Sariban¹,

Wu²,

Erickson³

et al. 1985

Mol. Cell. Biol.

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“…Because for cancer chemotherapeutic agents the drug concentrations that are of most interest are those that produce cell killing, the result of IC 75 values is thought to be more important than those of IC 50 . 29) In conclusion, BrdUrd effectively enhanced the antitumor effect of CPA in mice bearing L1210 ascites tumors. MTT assays in vitro partly reproduced the combined effect.…”

Section: Discussionmentioning

confidence: 99%

“…22,23) Statistical Analysis The statistical analysis was performed using the StatView version 5 program (Hulinks, Tokyo, Japan). Scheffe's F test was performed to compare the survival times of the mice, and pϽ0.05 was considered significant.…”

mentioning

confidence: 99%

Combined Antitumor Effect of Cyclophosphamide and Bromodeoxyuridine in BDF1 Mice Bearing L1210 Ascites Tumors

Kagawa

Noge

Higashigawa

et al. 2008

Biological & Pharmaceutical Bulletin

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Halogenated pyrimidines are incorporated in place of thymidine in DNA of replicating cells, making the cells more susceptible to the effects of radiation. 5-Bromo-2Ј-deoxyuridine (BrdUrd) has been clinically used as a radiosensitizer to enhance the tumor killing effect of radiation therapy. [1][2][3][4] The radiosensitizing effect of halogenated pyrimidines on mammalian cells in vitro is closely associated with the amount of drug incorporated into DNA. 5) Alkylating agents, such as cyclophosphamide (CPA), are widely used to treat a broad spectrum of malignancies, including both solid tumors and hematological malignancies. 6,7) CPA is converted by hepatic cytochrome P450 metabolic enzymes via two major pathways. 8) The first involves 4-hydroxylation to the active metabolite, 4-hydroxycyclophosphamide (4-OH-CPA). This conversion is carried out predominantly by cytochrome P450 CYP2B6 in humans. 9,10) 4-OH-CPA exists in equilibrium with aldophosphamide, which is broken down to form the DNA cross-linking agent phosphoramide mustard and the toxic metabolite acrolein. [11][12][13] The alternative pathway involves a CYP3A4-mediated N-dechloroethylation of CPA to form the inactive metabolite 3-dechloroethylcyclophosphamide (DECP) and the toxic byproduct chloroacetaldehyde. 11,14,15) In humans, this pathway is secondary to the activation pathway and accounts for less than 10% of the dose. 13) Alkylating agents undergo a transformation to produce highly reactive and positively charged ions. These ions can then form covalent bonds with electron-rich sites on biological molecules, such as nucleic acids, proteins, and amino acids. 16) Irradiation may cause the ablation of both singleand double-stranded DNA, degeneration or loss of bases, and intercalation of DNA and/or chromosomal protein. The actions of alkylating agents appear to have some similarities to those of gamma ray radiation. A previous in vitro report showed that pretreatment with iododeoxyuridine (IdUrd) or BrdUrd enhanced the cytotoxicity of various antineoplasmic agents, such as melphalan, cisplatin, doxorubicin, and bleomycin. 17) However, the mechanism of halopyrimidine's chemosensitizing effect is still unclear. There have been few in vivo studies on the combined antitumor effects of halogenated pyrimidines and alkylating agents. We investigated here the combined effect of BrdUrd and CPA, a bifunctional alkylating agent, on life span in L1210 ascites tumor-bearing mice and cytotoxicity in cultured L1210 cells using an MTT assay. Life Prolongation Study Male BDF1 mice were purchased from Shionogi Pharmaceutical Co., Ltd. and kept at Mie University Animal Center under constant conditions (a 12 h light : 12 h dark regimen with Oriental Chow pellet food and water freely available). L1210 leukemia cells were obtained from Shionogi Pharmacological Laboratory, Osaka, Japan and maintained in BDF1 mice by weekly intraperitoneal (i.p.) passage as previously described. 18) Experimental mice received an i.p. injection of 1ϫ10 6 ascites tumor cells in saline on Day 0. Se...

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“…Hydroxy harnstoff inhibiert nachhaltig die Ribonucleotid-Reduktase und somit den intrazellulären Spiegel der dCTP. Dadurch wird umgekehrt die Bildung von Ara-CTP, dem aktiven Metabolit des Ara-C, erhöht [9]. In einer vorausgegangenen Pilotstudie mit diesem Protokoll wurden bei 13 Patienten (> 65 Jahre) …”

Section: Wissenschaftlicher Hintergrund Und Fragestellungunclassified

AML-7-Studie zum Wert einer intensiven Remissionsinduktion bei alten Patienten mit akuter myeloischer Leukämie

Jehn

Löwenberg

1985

Oncol Res Treat

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Die Aggressivität moderner Therapie-Protokolle zur Behandlung der akuten myeloischen Leukamie stellt für alte Menschen wegen der toxischen Nebenwirkungen ein erhebliches Risiko dar. Die meisten Studien mit dieser Fragestellung deuten darauf hin, daß sich mit zunehmendem Lebensalter ( > 60 Jahre) die Behandlungserfolge deutlich verschlechtern. Es soil deshalb in einer multizentrischen Studie prospektiv die Überlebenszeit und Lebensqualität zweier verschiedener Behandlungsstrategien untersucht werden: zum einen unmittelbar einsetzende intensive Remissionsinduktion mit Daunomycin und Cytosin Arabinosid, zum anderen eine abwartende Haltung mit ausschließlich supportiven Maßnahmen und erst bei deutlicher Verschlechterung des klinischen und hämatologischen Befundes eine palliative Zytoreduktion unter Verwendung von Hydroxyharnstoff und Ara C. In den ersten 8 Monaten nach Aktivierung der Studie wurden 27 Patienten eingebracht, von denen 13 in den Arm I und 14 in den Arm II randomisiert wurden. Es ist zu früh, Ergebnisse mitzuteilen.

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Synergistic interaction between 1-beta-D-arabinofuranosylcytosine, thymidine, and hydroxyurea against human B cells and leukemic blasts in vitro.

Cited by 27 publications

References 37 publications

Interrelationships of protein and DNA syntheses during replication of mammalian cells.

Interrelationships of protein and DNA syntheses during replication of mammalian cells.

Combined Antitumor Effect of Cyclophosphamide and Bromodeoxyuridine in BDF1 Mice Bearing L1210 Ascites Tumors

AML-7-Studie zum Wert einer intensiven Remissionsinduktion bei alten Patienten mit akuter myeloischer Leukämie

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