Enhanced cytogenetic and antitumor effects by 9‐nitrocamptothecin and antineoplastics

Karaberis, E.; Mourelatos, D.

doi:10.1002/(sici)1520-6866(2000)20:3<141::aid-tcm5>3.3.co;2-4

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“…High rates of SCE caused by both doses of irinotecan are also indirect evidence of a large quantity of single‐ and double‐strand DNA breaks produced by treatment. These results are in agreement with the reports of other authors [44–46]. Besides an increased SCE frequency, irinotecan caused a delay in lymphocyte proliferation in vitro .…”

Section: Discussionsupporting

confidence: 93%

Irinotecan Toxicity to Human Blood Cells in vitro: Relationship between Various Biomarkers

Kopjar

Želježić

Vrdoljak

et al. 2007

Basic Clin Pharma Tox

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Toxic effects of the antineoplastic drug irinotecan on human blood cells at concentrations of 9.0 µ g/ml and 4.6 µ g/ml were evaluated in vitro . Using the alkaline and neutral comet assay significantly increased levels of primary DNA damage in lymphocytes were detected. The induction of apoptosis/necrosis, as determined by a fluorescent assay, was also notably increased. Cytogenetic outcomes of the treatment were assessed by the analysis of structural chromosome aberrations and fluorescence in situ hybridization. A significantly higher incidence of chromatid breaks and complex quadriradials was observed. Painted chromosomes 1, 2 and 4 were equally involved in translocations, but only the chromosome 1 was involved in the formation of quadriradials. Sister chromatid exchange analysis was performed in parallel with the analysis of lymphocyte proliferation kinetics. The higher concentration of irinotecan caused almost seven-time increase, while the lower one caused a five-time increase of the basal sister chromatid exchange frequency, accompanied with significant lowering of the lymphocyte proliferation index. Using the cytokinesis-block micronucleus assay, a dose-dependent increase in micronucleus frequency along with the formation of nuclear buds and nucleoplasmic bridges was noticed. Inhibitory effects of irinotecan on enzyme acetylcholinesterase (AChE) were studied in erythrocytes. An IC 50 value of 5.0 × 10 − 7 was established. Irinotecan was found to be strong inhibitor of the acetylcholine hydrolysis and to cause a continuous decrease of catalytic activity of AChE. The results obtained on a single donor may contribute to the understanding of irinotecan toxicity, but further in vitro and in vivo studies are essential in order to clarify remaining issues, especially on possible interindividual variability in genotoxic responses to the drug. Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin; CPT-11) is clearly one of the most important new anticancer drugs developed in the last few decades. It is a member of the camptothecin drug family [1]. Irinotecan is a pro-drug that is biotransformed by tissue and serum carboxylesterases to an active metabolite, SN-38 (7-ethyl-10-hydroxycamptothecin) that has a 100-1000-time higher cytotoxic and antitumour activity [2]. It acts as an inhibitor of the nuclear enzyme topoisomerase I, which is involved in cellular DNA replication and transcription. During replication, topoisomerase I mediates the relaxation of super-coiled DNA, and its inhibition results in breakage of the DNA chain and likely induces apoptosis. Irinotecan and SN-38 both bind to the topoisomerase I-DNA complex and prevent religation of single-strand breaks [3]. Irinotecan has undergone extensive clinical investigation worldwide and demonstrated potent activity against many types of human cancer, but is particularly active in the treatment of gastrointestinal and pulmonary malignancies [1][2][3][4].The principal dose-limiting toxicity of irinotecan is diarrhoea. It either...

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Section: Discussionsupporting

confidence: 93%

Irinotecan Toxicity to Human Blood Cells in vitro: Relationship between Various Biomarkers

Kopjar

Želježić

Vrdoljak

et al. 2007

Basic Clin Pharma Tox

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“…These derivatives employ tertiary amine cations to improve solubility and subsequently improve lactone stability. Currently, the CPTsnotably topotecan, − irinotecan, − 9-aminocamptothecin, , 9-nitrocamptothecin , and belotecanare being investigated for use as a late-stage therapy either alone or in combination therapies.…”

Section: Introductionmentioning

confidence: 99%

Cancer Therapies Utilizing the Camptothecins: A Review of the in Vivo Literature

2010

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This review summarizes the in vivo assessment--preliminary, preclinical, and clinical--of chemotherapeutics derived from camptothecin or a derivative. Camptothecin is a naturally occurring, pentacyclic quinoline alkaloid that possesses high cytotoxic activity in a variety of cell lines. Major limitations of the drug, including poor solubility and inactivity at physiological conditions, prevent full clinical utilization. Camptothecin remains at equilibrium in an active lactone form and inactive hydrolyzed carboxylate form. The active lactone binds to DNA topoisomerase I cleavage complex, believed to be the single site of activity inhibiting DNA religation, resulting in apoptosis. A series of small molecule camptothecin derivatives have been developed that increase solubility, lactone stability and bioavailability to varying levels of success. A number of macromolecular agents have also been described wherein camptothecin(s) are covalently appended or non-covalently associated with the goal of improving solubility and lactone stability, while taking advantage of the tumor physiology to deliver larger doses of drug to the tumor with lower systemic toxicity. With the increasing interest in drug delivery and polymer therapeutics, additional constructs are anticipated. The goal of this review is to summarize the relevant literature for others interested in the field of camptothecin-based therapeutics, specifically in the context of biodistribution, dosing regimens, and pharmacokinetics with the desire of providing a useful source of comparative data. To this end, only constructs where in vivo data is available are reported. The review includes published reports in English through mid-2009.

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Enhanced cytogenetic and antitumor effects by 9‐nitrocamptothecin and antineoplastics

Cited by 2 publications

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Irinotecan Toxicity to Human Blood Cells in vitro: Relationship between Various Biomarkers

Irinotecan Toxicity to Human Blood Cells in vitro: Relationship between Various Biomarkers

Cancer Therapies Utilizing the Camptothecins: A Review of the in Vivo Literature

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