Clinical use of topoisomerase I inhibitors in anticancer treatment

Rodríguez‐Galindo, Carlos; Radomski, Kristine M.; Stewart, Clinton F.; Furman, Wayne L.; Santana, Victor M.; Houghton, Peter J.

doi:10.1002/1096-911x(20001001)35:4<385::aid-mpo1>3.3.co;2-5

Cited by 9 publications

(9 citation statements)

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“…31 Topotecan also can be combined with topoisomerase II inhibitors or alkylating agents, which reportedly act synergistically with topotecan. 32 The pharmacokinetics of topotecan in this study were consistent with those observed previously in children with solid tumors 8 and children with ALL. 9 We monitored the topotecan plasma concentration of 1 patient who had renal failure and successfully adjusted the second dose to 30% of the starting dose on the basis of a topotecan clearance rate that was approximately 30% of the population mean.…”

Section: Discussionsupporting

confidence: 88%

Phase II study of topotecan in combination with dexamethasone, asparaginase, and vincristine in pediatric patients with acute lymphoblastic leukemia in first relapse

Hijiya

Stewart

Zhou

et al. 2008

Cancer

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BACKGROUND. The authors evaluated the response rate, toxicity, and pharmacokinetics of topotecan given before standard induction therapy for childhood acute lymphoblastic leukemia (ALL) in first relapse. METHODS. Patients received topotecan (2.4 mg/m2 daily as a 30‐minute infusion) for 5 days before induction therapy with dexamethasone, vincristine, and asparaginase (native or pegylated Escherichia coli). The pharmacokinetics of topotecan were measured with the first dose of treatment in 23 patients. RESULTS. Twenty‐eight of 31 patients with circulating blast cells were evaluable for response to topotecan. Twenty‐five patients (89.3%) had a response (>25% decrease in circulating blast cells). The leukocyte count (P = .0001) and blast cell count (P = .0009) declined significantly during topotecan therapy. The median (range) topotecan lactone area under the concentration‐time curve after the first dose was 85.4 L/hour/m2 (range, 38.7–229.3 L/hour/m2). At the end of induction, 23 patients (74.2%) had a complete response, 1 patient (3.2%) had a partial response, 5 patients (16.1%) had no response, and 2 patients had died of infection. Six of the 17 patients who were studied for minimal residual disease (MRD) achieved MRD‐negative status at the end of induction. The main toxicities were hematologic, gastrointestinal, and hepatic. The estimated 5‐year survival rate, event‐free survival rate, and cumulative incidence of second relapse were 24.1% ± 7.9%, 18.2% ± 7.4%, and 22.8% ± 8.7%, respectively, in the 29 patients who had a hematologic first relapse. CONCLUSIONS. A regimen comprising single‐agent topotecan given with a standard 3‐drug combination was effective in inducing remission in pediatric patients with relapsed ALL and was tolerated well. Cancer 2008. © 2008 American Cancer Society.

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Section: Discussionsupporting

confidence: 88%

Phase II study of topotecan in combination with dexamethasone, asparaginase, and vincristine in pediatric patients with acute lymphoblastic leukemia in first relapse

Hijiya

Stewart

Zhou

et al. 2008

Cancer

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“…Besides colorectal cancer, Top1 inhibitors are approved for the treatment of ovarian and small cell lung carcinoma (SCLC) (16). Clinical trials have been conducted for Top1 inhibitors (both as monotherapy and in combination studies with other anticancer agents) for many types of cancer, including colorectal, lung (non-SCLC and SCLC), ovarian, breast, and chronic myelomonocytic leukemia, with varying response rates (26). Topotecan has been shown to be effective in inducing remission when given before standard induction therapy for childhood acute lymphoblastic leukemia in the first relapse (27).…”

Section: Discussionmentioning

confidence: 99%

Topoisomerase I levels in the NCI-60 cancer cell line panel determined by validated ELISA and microarray analysis and correlation with indenoisoquinoline sensitivity

Pfister

Reinhold

Agama

et al. 2009

Molecular Cancer Therapeutics

145

141

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Topoisomerase I (Top1) is a proven target for cancer therapeutics, and the level of Top1 in tumors has been used as a biomarker for chemotherapeutic efficacy. In this study, we report the development and validation of a two-site enzyme chemiluminescent immunoassay for Top1, which we used to measure Top1 levels in the NCI-60 cancer cell line panel. Top1 levels ranged from 0.9 to 9.8 ng/mL/μg protein extract in these cell lines. Levels varied both within and between cancer types but were generally highest in colon cancer and leukemia cell lines and lowest in central nervous system and renal cancer cell lines. Top1 mRNA levels in the NCI-60 cell lines were also measured by microarray; mRNA values generally showed a good correlation with protein levels (Pearson correlation = 0.8). When these expression levels were compared with the activity of the indenoisoquinoline class of Top1 inhibitors across the NCI-60 cell panel, low levels of Top1 were associated with increased resistance to these drugs. The results of our studies indicate that our Top1 assay can be used to quantify Top1 levels in untreated cells as well as cells treated with Top1 inhibitors and that the assay has the potential to be adapted for use in predicting clinical response to Top1-active antineoplastic agents.

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“…Treatment with the Top1 inhibitor camptothecin (CPT), increases the half‐life of cleavage complexes and therefore the likelihood of their conversion into Top1‐associated SSBs and DSBs. This property of CPT and related compounds make them valuable as anticancer agents (Rodriguez‐Galindo et al , 2000).…”

Section: Introductionmentioning

confidence: 99%

TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo

Katyal

El‐Khamisy

Russell

et al. 2007

EMBO J

188

197

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Defective Tyrosyl-DNA phosphodiesterase 1 (TDP1) can cause spinocerebellar ataxia with axonal neuropathy (SCAN1), a neurodegenerative syndrome associated with marked cerebellar atrophy and peripheral neuropathy. Although SCAN1 lymphoblastoid cells show pronounced defects in the repair of chromosomal single-strand breaks (SSBs), it is unknown if this DNA repair activity is important for neurons or for preventing neurodegeneration. Therefore, we generated Tdp1 À/À mice to assess the role of Tdp1 in the nervous system. Using both in vitro and in vivo assays, we found that cerebellar neurons or primary astrocytes derived from Tdp1 À/À mice display an inability to rapidly repair DNA SSBs associated with Top1-DNA complexes or oxidative damage. Moreover, loss of Tdp1 resulted in age-dependent and progressive cerebellar atrophy. Tdp1 À/À mice treated with topotecan, a drug that increases levels of Top1-DNA complexes, also demonstrated significant loss of intestinal and hematopoietic progenitor cells. These data indicate that TDP1 is required for neural homeostasis, and reveal a widespread requisite for TDP1 function in response to acutely elevated levels of Top1-associated DNA strand breaks.

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Clinical use of topoisomerase I inhibitors in anticancer treatment

Cited by 9 publications

References 0 publications

Phase II study of topotecan in combination with dexamethasone, asparaginase, and vincristine in pediatric patients with acute lymphoblastic leukemia in first relapse

Phase II study of topotecan in combination with dexamethasone, asparaginase, and vincristine in pediatric patients with acute lymphoblastic leukemia in first relapse

Topoisomerase I levels in the NCI-60 cancer cell line panel determined by validated ELISA and microarray analysis and correlation with indenoisoquinoline sensitivity

TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo

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