Cytotoxicity and DNA damage associated with pyrazoloacridine in MCF-7 breast cancer cells

Grem, Jean L.; Politi, Pedro M.; Berg, Stacey L.; Benchekroun, Mohamed Nabil; Patel, Mahendra; Balis, Frank M.; Sinha, Birandra K.; Dahut, William; Allegra, Carmen J.

doi:10.1016/0006-2952(96)00130-x

Cited by 23 publications

(22 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results suggest that PZA may be an excellent drug choice in treating resistant tumors, or more importantly, in tumors where resistant tumor is likely to emerge. Consistent with this idea, others have reported that PZA exhibited activity against many different types of MDR tumors, such as Adriamycin-resistant sublines of P388 leukemia, B16 melanoma, and 16C mammary adenocarcinoma cells (6), as well as HL-60/ADR human promyelocytic leukemia cells and MCF-7/AD10 human breast cancer cells (8). The results summarized here confirm these previous results and also suggest that PZA can completely circumvent drug resistance in AD 300 cells when used in combination with VP-16 or topotecan, as well as partially restore drugs resistance when combined with DOX.…”

Section: Discussionmentioning

confidence: 55%

“…These studies would suggest that synergistic cytotoxicity of PZA and doxorubicin, topotecan, or VP-16 may be due to their combined effects on DNA and RNA synthesis and/or multilevel therapeutic targets. It is important to recognize that others have shown that PZA retained similar activity against the Topo I-deficient P388/CPT45 and the Topo II-deficient HL-60 sublines when compared with the parental cell lines (8,30,31) and yeast cells lacking either Topo I or II (9). These results argue that cytotoxicity of PZA does not relate directly with topoisomerase activity.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, PZA maintains its activity against several phenotypes of drug-resistant cancer cells including those overexpressing P-glycoprotein, multidrug-resistance protein, and cells deficient in topoisomerase I (Topo I) and II (Topo II; Refs. 6,7,8). This unusual activity of PZA is associated with inhibition of DNA and RNA syntheses, damage to both nascent and parental DNA (8), as well as an ability to inhibit Topo I and II in a manner distinct from that of past Topo I-and II-targeting agents (8,9).…”

Section: Introductionmentioning

confidence: 99%

“…6,7,8). This unusual activity of PZA is associated with inhibition of DNA and RNA syntheses, damage to both nascent and parental DNA (8), as well as an ability to inhibit Topo I and II in a manner distinct from that of past Topo I-and II-targeting agents (8,9).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Synergistic Cytotoxicity of Pyrazoloacridine with Doxorubicin, Etoposide, and Topotecan in Drug-Resistant Tumor Cells

Krishan

Nie

et al. 2004

Clinical Cancer Research

View full text Add to dashboard Cite

Pyrazoloacridine (NSC 366140, PD115934, PZA) is a new class of acridine anticancer agents under investigation in Phase II clinical trials in patients with advanced cancers. Although poor responses in patients to the treatment with PZA alone have been observed, this class of agents remains of interest because of its distinct mechanism of action from other topoisomerase poisons. Therefore, the combination of PZA with conventional anticancer agents presents an attractive approach to treat drug-resistant human tumors. In the present study, the cytotoxic effects of PZA combined with doxorubicin, topotecan, and etoposide were determined using paired parental and doxorubicin-resistant human colon carcinoma (SW-620 and SW620/AD-300) and breast cancer cell lines (MCF-7 and MCF-7/TH). Cytotoxicity was measured by soft agar clonogenic assays. Dose effect and combination effects were analyzed by the method of Chou and Talalay. The combination of PZA with doxorubicin, topotecan, and etoposide in fixed ratios demonstrated synergistic cytotoxicity on both SW-620 and SW620/AD-300 cell lines. The combination of PZA with doxorubicin also exhibited synergistic cytotoxicity against both MCF-7 and MCF-7/TH cell lines. The mechanism of synergism appeared independent of topoisomerase I and II inhibition, and interference with protein-DNA complexes. Strategies to define optimal drug combinations are proving to be of significant value when considering potential clinical applications of new and established agents.

show abstract

Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Synergistic Cytotoxicity of Pyrazoloacridine with Doxorubicin, Etoposide, and Topotecan in Drug-Resistant Tumor Cells

Krishan

Nie

et al. 2004

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…Consistent with this observation, PZA inhibited RNA synthesis more effectively than DNA synthesis (1). PZA inhibited topoisomerases I and II by a mechanism that is distinct from other dual topoisomerase I/II inhibitors (5), possibly due to direct enzyme inhibition (5,6). PZA also induced apoptosis in p53-deficient Hep3B human hepatoma cells (7).…”

Section: Introductionmentioning

confidence: 99%

The Metabolism of Pyrazoloacridine (NSC 366140) by Cytochromes P450 and Flavin Monooxygenase in Human Liver Microsomes

Reid¹,

Walker²,

Miller³

et al. 2004

Clinical Cancer Research

View full text Add to dashboard Cite

SyntheticDNA‐Targeted Chemotherapeutic Agents And Related Tumor‐Activated Prodrugs

Denny

2010

Burger's Medicinal Chemistry and Drug Discovery

View full text Add to dashboard Cite

Synthetic drugs have always played an important role in cancer therapy. The first systemic anticancer drugs were synthetic DNA alkylating agents and DNA antimetabolites. The original antimetabolites such as cytosine arabinoside and 5‐fluorouracil have been augmented by more recent compounds such as gemcitabine, fludarabine, cladribine, and pentostatin, which inhibit DNA polymerase action during DNA synthesis. A new development is the related compounds deazacytidine and decitabine, which inhibit reactivate silenced genes by inhibition of cytosine methylation. Nitrogen mustards, platinum complexes, nitrosoureas, and triazene‐based DNA‐methylating agents are direct DNA‐modifying agents that still play an important role in clinical treatment. Methotrexate and more recent lipophilic analogs, together with older drugs such as 5‐fluorouracil, are used as inhibitors of different enzymes in the folate pathway necessary for the synthesis of pyrimidine nucleotides. The potent activity of natural products such as doxorubicin also led to the development of the synthetic topoisomerase inhibitors that are now another important group of drugs whose therapeutic effects are due to enzyme‐mediated DNA modification. Finally, an increasing understanding of tumor physiology and genetics has allowed the development of tumor‐activated prodrugs of DNA‐active agents. Using hypoxia, gene therapy or antibody targeting to activate such prodrugs specifically in tumor tissue has the potential to increase the therapeutic index of these agents by limiting the exposure of sensitive nontumor cell populations.

show abstract

Cytotoxicity and DNA damage associated with pyrazoloacridine in MCF-7 breast cancer cells

Cited by 23 publications

References 14 publications

Synergistic Cytotoxicity of Pyrazoloacridine with Doxorubicin, Etoposide, and Topotecan in Drug-Resistant Tumor Cells

Synergistic Cytotoxicity of Pyrazoloacridine with Doxorubicin, Etoposide, and Topotecan in Drug-Resistant Tumor Cells

The Metabolism of Pyrazoloacridine (NSC 366140) by Cytochromes P450 and Flavin Monooxygenase in Human Liver Microsomes

SyntheticDNA‐Targeted Chemotherapeutic Agents And Related Tumor‐Activated Prodrugs

Contact Info

Product

Resources

About