Bleomycin—mode of action with particular reference to the cell cycle

Twentyman, Peter R.

doi:10.1016/0163-7258(83)90022-0

Cited by 67 publications

(31 citation statements)

References 82 publications

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“…However, more cells were stained in the SAM and RAM of jhs1, which suggests that the DNA damage response was greater in these cells and that more cells underwent G 2 cell-cycle arrest in the jhs1 mutant. In addition, we treated wild-type and jhs1 mutant plants with 1.0 mM HU, which primarily induces G 1 arrest, but also induces G 2 arrest (Culligan et al, 2004); aphidicolin, which inhibits the replicative DNA polymerases d and « and induces G 2 arrest (Culligan et al, 2004); and zeocin, which induces G 2 arrest (Twentyman, 1983). HU treatment can induce the GUS level in the RAM of the wild type, but not in the RAM and SAM of jhs1.…”

Section: The Frequency Of Homologous Recombination Is Increased In Jhs1mentioning

confidence: 99%

A DNA2 Homolog Is Required for DNA Damage Repair, Cell Cycle Regulation, and Meristem Maintenance in Plants

2016

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Plant meristem cells divide and differentiate in a spatially and temporally regulated manner, ultimately giving rise to organs. In this study, we isolated the Arabidopsis jing he sheng 1 (jhs1) mutant, which exhibited retarded growth, an abnormal pattern of meristem cell division and differentiation, and morphological defects such as fasciation, an irregular arrangement of siliques, and short roots. We identified JHS1 as a homolog of human and yeast DNA Replication Helicase/Nuclease2, which is known to be involved in DNA replication and damage repair. JHS1 is strongly expressed in the meristem of Arabidopsis. The jhs1 mutant was sensitive to DNA damage stress and had an increased DNA damage response, including increased expression of genes involved in DNA damage repair and cell cycle regulation, and a higher frequency of homologous recombination. In the meristem of the mutant plants, cell cycle progression was delayed at the G2 or late S phase and genes essential for meristem maintenance were misregulated. These results suggest that JHS1 plays an important role in DNA replication and damage repair, meristem maintenance, and development in plants.

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Section: The Frequency Of Homologous Recombination Is Increased In Jhs1mentioning

confidence: 99%

A DNA2 Homolog Is Required for DNA Damage Repair, Cell Cycle Regulation, and Meristem Maintenance in Plants

2016

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“…Figure 3 shows the survival curve for stationary phase SCC-25 cells exposed to various concentrations of bleomycin. The survival curve is biphasic with an initial sensitive phase and a less sensitive second phase, as is common for many cell lines (Twentyman, 1984). After stationary phase SCC-25 cells were exposed to 100pgml-1 of bleomycin for 1 h, the drug was removed and the cells were allowed various periods for PLD recovery.…”

Section: Resultsmentioning

confidence: 99%

“…The ability of mammalian cells to recover from bleomycininduced damage has been well-documented both in vitro and in vivo (Barranco & Townsend, 1986). This process can be inhibited with actinomycin D, ethanol and hyperthermia (Barranco, 1978;Twentyman, 1984) or under hypoxic conditions by misonidazole (Korbelik et al, 1985). More recently it has been shown that some platinum complexes can inhibit the recovery of V79 cells from radiation-induced cell kill (O'Hara et al, 1986).…”

Section: Discussionmentioning

confidence: 99%

“…The clinical significance of PLDR, defined here as recovery of survival before subculture, has remained controversial (Twentyman, 1984;Weichselbaum et al, 1982Weichselbaum et al, , 1984 but it seems reasonable that drug combinations which inhibit the ability of tumour cells to repair significant portions of druginduced damage will lead to improved clinical efficacy. The ability of mammalian cells to recover from bleomycininduced damage has been well-documented both in vitro and in vivo (Barranco & Townsend, 1986).…”

Section: Discussionmentioning

confidence: 99%

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Platinum-dye complexes inhibit repair of potentially lethal damage following bleomycin treatment

Wang

Herman²,

Ba³

1989

Br J Cancer

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Summary Several new complexes of platinum with positively charged cellular dyes have been synthesised in an effort to find chemotherapeutic drugs with increased antitumour cytotoxicity. As part of this effort, the direct cytotoxicities of some of these complexes as well as their ability to inhibit bleomycin potentially lethal damage repair (PLDR) was studied in vitro in a squamous cancer cell line of human origin . All of the new agents were more cytotoxic against exponentially growing than against plateau phase cell cultures. Exposure of cells to non-lethal drug concentrations for between 1 and 6h led to measurable inhibition of bleomycin PLDR in the case of each drug tested. In order of decreasing ability to inhibit bleomycin PLDR, Pt(fast black)2, Pt(thioflavin)2 and Pt(thionin)2 were more effective than CDDP, while Pt(methylene blue)2, Pt(Rh-123)2 and Pt(pyronin y)2 were less effective. The most directly cytotoxic agents were Pt(thioflavin)2, Pt(pyronin Y)2 and Pt(Rh-123)2 which also proved to be the least selectively toxic drugs towards exponential versus plateau phase cells. These results indicate that several of the new platinum complexes may be effective cytotoxic agents as well as effective inhibitors of DNA repair process following exposure of cells to other DNA interactive modalities.The glycopeptide antibiotic bleomycin has demonstrated clinical usefulness in the treatment of squamous cell cancer of the head and neck (SCCHN) (Turrisi et al., 1978), testicular tumours (Einhorn & Donahue, 1977) and lymphomas (Coltman et al., 1978). It is used in combinations with other agents because bleomycin does not exhibit dose limiting haematopoietic toxicity (Hubbard et al., 1975). When used as a single agent, however, complete response rates are relatively low and the emergence of drug resistance is a common problem (Crooke & Bradner, 1976).To various extents, mammalian tumour cells have the capacity to repair drug-and radiation-induced damage. The ability of cells to recover from potentially lethal damage has been modelled in vitro by maintaining cells in conditions which prevent them from proliferating for various times and thereby allowing time for repair processes to take place (Barranco & Townsend, 1986).Solid tumours and slow growing lymphomas are likely to contain large populations of non-cycling cells, which may have the capacity to repair potentially lethal damage and contribute to regrowth of the tumour. An in vitro system containing cells in stationary phase may be more analogous to the in vivo situation than are cells in exponential growth. Such an experimental model can be created by growing monolayer cell cultures to confluency under conditions of constant medium renewal without subculture. These stationary phase cultures contain a large fraction of non-cycling, but potentially clonogenic, cells (Hahn & Little, 1972). In such model systems, time dependent enhancement of cell survival observed with longer pre-subculture intervals following exposure to cytotoxic agents can be inferred as due to poten...

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“…DNA lesions are believed to be a principal cause of the lethal properties of the chemical action of bleomycin group antibiotics (e.g., see references 2, 3, 33-35, 39, 44, and 73), and there is considerable interest in the growth phase (review by Twentyman [70]) during which the glycopeptides are selectively pernicious. In spheroids, noncycling Chinese hamster V79 cells in inner layers were more sensitive to bleomycin than proliferating cells in outer layers (68).…”

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Growth phase dependency of chromatin cleavage and degradation by bleomycin

Moore

Jones

Wall

1989

Antimicrob Agents Chemother

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Preferential cleavage of Saccharomyces cerevisiae chromosomes in internucleosomal (linker) regions and nonspecific degradation of chromatin by an anticancer antibiotic which degrades DNA were investigated and found to increase in consecutive stages of growth. Cleavage of DNA in internucleosomal regions and intensities and multiplicities of nucleosomal bands were dependent on drug concentration, growth phase of the cells, and length of incubation. Cellular DNA was least degraded during logarithmic phase. After cells progressed only one generation in logarithmic phase, low concentrations (6.7 x 10-7 to 3.4 x 10-6 M) of bleomycin produced approximately three to seven times more DNA breaks. Internucleosomal cleavage was highest, and the most extended oligonucleosomal series and extensive chromatin degradation were observed during stationary phase. It is concluded that the growth phase of cells is critical in determining amounts of the highly preferential cleavage in internucleosomal regions and overall breakage and degradation of DNA. Mononucleosomal bands were most intense, indicating the greatest accumulation of DNA of this size. Mean mononucleosomal lengths were 165.9 + 3.9 base pairs, in agreement with yeast mononucleosomal lengths. As high-molecular-weight chromatin was digested by bleomycin, oligonucleosomes and, eventually, mononucleosomes became digested. Therefore, it is also concluded that bleomycin degradation of oligonucleosomes and trimming of DNA linker regions proceed to degradation of the monosomes (core plus linker DNA).We consider in the current investigation that the growth phase of cells could be a crucial factor in determining lesions produced in cellular chromatin. The chromatin conformation characteristic for chromosomal organization in eucaryotic cells certainly can be very important in determining the nature and extent of chemical reactivity with genomic structures. For example, DNA is preferentially cleaved in internucleosomal (linker) regions of chromatin in isolated mammalian nuclei (18,22,23), in intact human K562 cells (46), and in Saccharomyces cerevisiae (40) by the unique chemical action of the low-molecular-weight glycopeptides (Mr, approximately 1,500 to 1,600 [ Fig. 1]) in the bleomycin family of anticancer antibiotics (4,12,14,20,21,30,31,39,47,59,60,62). Bleomycins form single-and double-strand breaks in DNA (e.g., see references 2, 7, 15, 16, 29, 39, 41, 44, and 60 sensitive to killing by bleomycin in plateau phase than when growing exponentially, but the reverse was true for mouse tumor cells in an earlier study (71) and for Chinese hamster V79 (28), Burkitt's lymphoma (32,66), and human colon carcinoma (8) (10,36,39,44,51) from starting inocula of 8 x 106 cells per ml. Cells were harvested by centrifugation at 4°C in a Dupont Sorvall RC-SB SS34 rotor at 2,500 x g and washed twice with deionized water.

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Bleomycin—mode of action with particular reference to the cell cycle

Cited by 67 publications

References 82 publications

A DNA2 Homolog Is Required for DNA Damage Repair, Cell Cycle Regulation, and Meristem Maintenance in Plants

A DNA2 Homolog Is Required for DNA Damage Repair, Cell Cycle Regulation, and Meristem Maintenance in Plants

Platinum-dye complexes inhibit repair of potentially lethal damage following bleomycin treatment

Growth phase dependency of chromatin cleavage and degradation by bleomycin

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