Chromosome-mediated gene transfer of hydroxyurea resistance and amplification of ribonucleotide reductase activity.

Lewis, William H.; Srinivasan, Prakash

doi:10.1128/mcb.3.6.1053

Cited by 33 publications

(11 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1982, andStark andWahl, 1984). The karyo type of the hydroxyurea-resistant hamster cell line 600H shows no evidence of homogeneously staining regions or double minute chromosomes (Lewis and Srinivasan, 1983). However, the cell line has a modal chromosome number of 23. having gained an extra chromosome 7.…”

Section: Discussionmentioning

confidence: 97%

“…1978, 1979;Akerblom et al, 1981). Cell lines selected in multiple selection steps for increasing resistance to hydroxyurea have been shown to have corresponding stepwise increases in RDR activity, and in some cell lines amplification of at least one of the two genes encoding RDR subunits, Ml and M2, has occurred (Lewis and Srinivasan, 1983;Thelander and Berg, 1986;Cocking et al, 1987;Sri nivasan et al. 1987;Wright et al.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Chromosomal assignment of amplified genes in hydroxyurea-resistant hamster cells

Tonin¹,

Stallings²,

Carman³

et al. 1987

Cytogenet Genome Res

View full text Add to dashboard Cite

We have shown previously that cDNAs for the Ml and M2 subunits of ribonucleotide reductase, ornithine decarboxylase (ODC), and p5–8, a 55,000-Dalton protein, hybridize to amplified genomic sequences in a highly hydroxyurea-resistant hamster cell line. We have extended these observations to include two additional, independently isolated, hydroxyurea-resistant cell lines: SC8, a single-step hamster ovary cell line, and KH450, a multistep human myeloid leukemic cell line, have also undergone genomic amplification for sequences homologous to ODC and p5–8 cDNAs. However, neither SC8 nor KH450 contains amplified genomic sequences homologous to an Ml cDNA probe. A panel of mouse-hamster somatic cell hybrids was used to map sequences homologous to Ml, M2, ODC, and 5–8 cDNAs in the hamster genome. The M2, ODC, and p5–8 cDNAs hybridized to DNA fragments that segregated with hamster chromosome 7. In contrast, Ml cDNA hybridized to DNA fragments that segregated with hamster chromosome 3. These data suggest that the genes RRM2, (M2), ODC, and p5–8, but not RRM1 (Ml), are linked and may have been co-amplified in the selection of the hydroxyurea-resistant hamster and human cell lines.

show abstract

Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

Chromosomal assignment of amplified genes in hydroxyurea-resistant hamster cells

Tonin¹,

Stallings²,

Carman³

et al. 1987

Cytogenet Genome Res

View full text Add to dashboard Cite

show abstract

“…We next sought to determine whether the appearance of pseudomitotic cells was dependent upon cellular or viral DNA replication. AD-infected HFs were either left untreated or maintained in the presence of 1 mM HU (to block only cellular DNA synthesis), 10 mM HU (to block cellular and viral DNA synthesis) (6,15,59), or 300 g of PFA/ml (to block only viral DNA synthesis) (97,99) before the cells were processed for immunofluorescence analysis with anti-␥tub1 and anti-IE1/IE2 antibodies. As expected, treatment with these drugs did not have any effect on IE1/IE2 expression, and similar, almostuniform infection based on IE1/IE2 positive cells was observed in all cultures.…”

mentioning

confidence: 99%

Global Analysis of Host Cell Gene Expression Late during Cytomegalovirus Infection Reveals Extensive Dysregulation of Cell Cycle Gene Expression and Induction of Pseudomitosis Independent of US28 Function

Hertel

Mocarski

2004

J Virol

136

129

View full text Add to dashboard Cite

Replication of human cytomegalovirus (CMV) depends on host cell gene products working in conjunction with viral functions and leads to a dramatic dysregulation of cell cycle gene expression. Comprehensive transcriptional profiling was used to identify pathways most dramatically modulated by CMV at late times during infection and to determine the extent to which expression of the viral chemokine receptor US28 contributed to modulating cellular gene expression. Cells infected with the AD169 strain of virus or a fully replication competent US28-deficient derivative (RV101) were profiled throughout the late phase of infection (50, 72, and 98 h postinfection). Although sensitive statistical analysis showed striking global changes in transcript levels in infected cells compared to uninfected cells, the expression of US28 did not contribute to these alterations. CMV infection resulted in lower levels of transcripts encoding cytoskeletal, extracellular matrix, and adhesion proteins, together with small GTPases and apoptosis regulators, and in higher levels of transcripts encoding cell cycle, DNA replication, energy production, and inflammation-related gene products. Surprisingly, a large number of cellular transcripts encoding mitosis-related proteins were upmodulated at late times in infection, and these were associated with the formation of abnormal mitotic spindles and the appearance of pseudomitotic cells. These data extend our understanding of how broadly CMV alters the regulation of host cell cycle gene products and highlight the establishment of a mitosis-like environment in the absence of cellular DNA replication as important for viral replication and maturation.Human cytomegalovirus (CMV) infection has a dramatic impact on the cell that starts immediately after infection (4) and continues through late times (34, 67). The replication cycle follows a temporal cascade of events that depends upon both viral and host cell functions. Viral DNA replication begins between 14 and 24 h postinfection (hpi), and release of progeny starts between 36 and 48 hpi, reaching maximal levels between 72 and 96 hpi (67). This process causes profound changes in host cell shape, metabolism, and gene transcription, components of which are suspected to be critical for efficient replication. Previous studies in primary fibroblasts have revealed the global impact of viral infection on signaling and transcriptional changes that start as early as 15 min and last as long as 48 hpi (4,16,50,51,85,112,113). These studies have largely focused on the immediate impact of the virus on cells and have revealed a dramatic upmodulation of cellular inflammatory and immune gene expression due to virus binding and penetration. Based on this work, selected cellular signaling events (51, 103) and cellular proteins (13,89,114) have been implicated as important regulators of infection. There has been a less concerted effort to understand the global impact of CMV infection at late times during infection (16), despite the fact that maximal modulation would be ...

show abstract

“…Likewise, overexpression of RRM2 resulted in increased in resistance to gemcitabine chemoresistance in lung (27) and pancreatic (28) cancer cells in vitro . In cell lines selected for resistance to hydroxyurea, increased RRM2 protein levels and ribonucleotide reductase activity were detected (29-31). Taken together, these findings suggest that alterations in RRM1 and RRM2 expression may confer resistance to chemotherapy and may be useful biomarkers for predicting and monitoring responses to various therapies including Triapine ® (32, 33).…”

Section: Discussionmentioning

confidence: 99%

A phase I study of Triapine® in combination with doxorubicin in patients with advanced solid tumors

Schelman¹,

Morgan-Meadows²,

Marnocha³

et al. 2008

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

Purpose-To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics and antitumor activity of Triapine ® administered in combination with doxorubicin.Study Design-Patients were treated with doxorubicin intravenously (IV) on day 1 and Triapine ® IV on days 1-4 of a 21-day cycle. The starting dose (level 1) was doxorubicin 60 mg/m 2 and Triapine ® 25 mg/m 2 . PK analysis was performed at various time-points before and after treatment.Results-Twenty patients received a total of 49 courses of treatment on study. At dose level 2 (doxorubicin 60 mg/m 2 , Triapine ® 45 mg/m 2 ), 2 patients experienced DLTs (febrile neutropenia, grade 4 thrombocytopenia). An additional 3 patients were enrolled at dose level 1 without initial toxicity. Enrollment then resumed at dose level 2a with a decreased dose of doxorubicin (45 mg/ m 2 ) with Triapine ® 45 mg/m 2 . The 2 patients enrolled on this level had 2 DLTs (diarrhea, CVA). Enrollment was planned to resume at dose level 1; however, the sixth patient enrolled to this cohort developed grade 5 heart failure (ejection fraction 20%, pretreatment EF 62%) after the second course. Thus, doxorubicin and Triapine ® were reduced to 45 mg/m 2 and 25 mg/m 2 , respectively (level 1a), prior to resuming enrollment at dose level 1, the MTD. The main drugrelated toxicity was myelosuppression. Non-hematologic toxicities included mild-to-moderate fatigue, grade 3 diarrhea and grade 4 CVA. There was one treatment-related death due to heart failure. While no objective responses were observed, subjective evidence of clinical activity was observed in patients with refractory melanoma and prostate cancer.Conclusions-Pretreated patients with advanced malignancies can tolerate the combination of Triapine ® and doxorubicin at doses that achieve subjective clinical benefit with the main treatment-related toxicities being myelosuppression and fatigue. The MTD was determined to be doxorubicin 60 mg/m 2 on day 1 and Triapine ® 25 mg/m 2 on days 1-4 of a 21 day cycle. KeywordsTriapine ® ; 3-aminopyridine-2-carboxaldehyde thiosemicarbazone; doxorubicin; phase I; ribonucleotide reductase * Corresponding author and address for reprint requests: University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, 600 Highland Avenue, K6/568. Madison, WI 53792, Phone (608) Fax (608) InroductionTriapine ® (3-aminopyridine-2-carboxaldehyde thiosemicarbazone) is a potent small molecule ribonucleotide reductase (RR) inhibitor that exerts its antineoplastic activity by inhibiting DNA synthesis and repair (1). Ribonucleotide reductase is an enzyme that is important for cell division and tumor growth (2-4), and the human RR has a tetrameric structure, composed of two non-identical homodimers (5). The RRM1 subunit contains a nucleotide binding site, and the RRM2 subunit contains a metal binding site. The RRM2 subunit is comprised of a non-heme iron and a tyrosine free radical, which are required for the enzymatic reduction of ribonucleotides (6). Therapeutic agents that inhibi...

show abstract

Chromosome-mediated gene transfer of hydroxyurea resistance and amplification of ribonucleotide reductase activity.

Cited by 33 publications

References 25 publications

Chromosomal assignment of amplified genes in hydroxyurea-resistant hamster cells

Chromosomal assignment of amplified genes in hydroxyurea-resistant hamster cells

Global Analysis of Host Cell Gene Expression Late during Cytomegalovirus Infection Reveals Extensive Dysregulation of Cell Cycle Gene Expression and Induction of Pseudomitosis Independent of US28 Function

A phase I study of Triapine® in combination with doxorubicin in patients with advanced solid tumors

Contact Info

Product

Resources

About