Toxicological testing of cytotoxic drugs (Review)

Colombo, Paolo; Gunnarsson, Kjell; Iatropoulos, Michael J.

doi:10.3892/ijo.19.5.1021

Cited by 22 publications

(28 citation statements)

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“…All the observed toxic effects after treatment with DTS-201 are typical of cytotoxic agents and are the same as those reported for free doxorubicin, but they occur at higher dose levels than with free doxorubicin (19). The main target organs of DTS-201 toxicity are bone marrow and the lymphoid tissues, the gastrointestinal tract and oral cavity, and the genital tract, as is the case for most cytotoxic anticancer agents and doxorubicin in particular (19). In rodents, the peripheral nervous system was also a key target, the animals systematically developing hind limb paralysis at toxic dose levels.…”

Section: Resultssupporting

confidence: 59%

“…After two consecutive injections, the MTD was found to be 50 mg/kg (f150 mg/m 2 ) and 40 mg/kg (f240 mg/m 2 ) in mice and rats, respectively. Comparing these values to those of doxorubicin documented in the literature, DTS-201 seems to be at least three to four times less toxic in rodents (6,19) and up to 8 to 9-fold less toxic in the dog (16,20).…”

Section: Resultsmentioning

confidence: 74%

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Preclinical Toxicity, Toxicokinetics, and Antitumoral Efficacy Studies of DTS-201, a Tumor-Selective Peptidic Prodrug of Doxorubicin

Ravel¹,

Dubois²,

Quinonero³

et al. 2008

Clinical Cancer Research

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Purpose: There is a clear clinical need for cytotoxic drugs with a lower systemic toxicity. DTS-201 (CPI-0004Na) is a peptidic prodrug of doxorubicin that shows an improved therapeutic index in experimental models. The purpose of the current study was to complete its preclinical characterization before initiation of phase I clinical trials. Experimental Design:The preclinical development program consisted of a detailed assessment of the general and cardiac toxicity profiles of DTS-201in mice, rats, and dogs, together with mass balance and antitumoral efficacy studies in rodents. Neprilysin and thimet oligopeptidase expression, two enzymatic activators of DTS-201, was also characterized in human breast and prostate tumor biopsies. Results: The target organs of DTS-201toxicity in rodents and dogs are typically those of doxorubicin, albeit at much higher doses. Importantly, chronic treatment with DTS-201 proved to be significantly less cardiotoxic than with doxorubicin at doses up to 8-fold higher in rats. The mass balance study showed that [ 14 C] DTS-201 does not accumulate in the body after intravenous administration. The improved therapeutic index of DTS-201compared with free doxorubicin was confirmed in three tumor xenograft models of prostate, breast, and lung cancer. Neprilysin and/or thimet oligopeptidase are expressed in all experimental human tumor types thus far tested as well as in a large majority of human breast and prostate tumor biopsies. Conclusion: DTS-201 gave promising results in terms of general toxicity, cardiovascular tolerance, and in vivo efficacy in xenograft mouse models compared with free doxorubicin. Taken together, these results and the confirmation of the presence of activating enzymes in human tumor biopsies provide a strong rationale for a phase I clinical study in cancer patients.

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Section: Resultssupporting

confidence: 59%

Section: Resultsmentioning

confidence: 74%

Preclinical Toxicity, Toxicokinetics, and Antitumoral Efficacy Studies of DTS-201, a Tumor-Selective Peptidic Prodrug of Doxorubicin

Ravel¹,

Dubois²,

Quinonero³

et al. 2008

Clinical Cancer Research

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“…Both neoplastic and non-neoplastic cells attempt to repair them. However, if unrepaired, DNA lesions may give rise to chromatid-type aberrations during S-phase and interfere with the transcription and replication of DNA, resulting in cytotoxic and mutagenic effects [3,4]. Growing evidence suggests that secondary neoplasms may arise as a late complication of successful chemotherapy [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Alkaline comet assay study with breast cancer patients: evaluation of baseline and chemotherapy-induced DNA damage in non-target cells

et al. 2006

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The sensitivity of the alkaline comet assay for the evaluation of baseline and treatment-induced DNA damage in white blood cells of breast cancer patients receiving adjuvant chemotherapy according to three conventional anthracycline- and cyclophosphamide-containing protocols was investigated. Additionally, baseline DNA damage in cancer patients was compared with the levels of DNA damage recorded in healthy women. Altogether 30 patients with diagnosed breast cancer and 30 female blood donors with no known familial history of breast cancer participated in the study. Alkaline comet assay was performed according to standard protocol and DNA migration in peripheral blood leukocytes was measured by a computer-based image analysis system. For each subject the frequency of "damaged" cells, i.e., long-tailed nuclei (LTN) with tail length exceeding 95th percentile for the considered parameter among controls, is also reported. Breast cancer patients had significantly increased background levels of DNA damage in their peripheral blood leukocytes as compared to healthy women. Prior to the chemotherapy, a majority of patients showed a statistically significant increase in the number of LTN compared to healthy blood donors. Marked interindividual variations in baseline DNA damage among patients were recorded, some of them related to the disease stage and status. The present study confirmed the alkaline comet assay as a sensitive technique able to detect significantly elevated DNA migration in blood cells of patients already one hour after completion of the first cycle of chemotherapy. Administration of antineoplastic drugs in three chemotherapy protocols studied induced a similar increase of primary DNA damage in nontarget cells. The evaluation of the LTN frequencies indicates the best response to the protocol containing cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Our results point to the significance of simultaneous evaluation of DNA migration and frequency of LTN in the same subject and approved the use of alkaline comet assay as a suitable method for the routine detection of critical DNA lesions produced after administration of antineoplastic drugs in the clinical settings.

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“…Quinones form the second largest class of antitumor agents approved for clinical use in the U.S.A. and several antitumor quinones are in different stages of clinical and preclinical development [1,2]. A common feature in quinone-containing drugs is their ability to undergo reversible redox reactions to form semiquinone and oxygen radicals [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

“…The semiquinone can also be formed by a conproportionation reaction between a quinone and a hydroquinone, reaction (1) (the opposite of reaction 1 is the semiquinone disproportionation reaction). (1) The antitumor effect of some quinone-containing drugs is known to be enhanced upon exposure to ultrasound [6,7]. A synergistic effect of cell killing for hematoporphyrin combined with ultrasound has been ascribed to the formation of the superoxide anion radical, O 2 ·− , because cell damage was suppressed by superoxide dismutase (SOD) [2].…”

Section: Introductionmentioning

confidence: 99%

Quinone-enhanced sonochemical production of nitric oxide from s-nitrosoglutathione

Alegrı́a

Dejesús-Andino

Sanchez-Cruz

2009

Ultrasonics Sonochemistry

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Sonolysis at 75 kHz of argon-and air-saturated aqueous solutions at pH 7.4 containing snitrosogluthathione (GSNO) enhances the production rate of nitric oxide (NO). The quinones, anthraquinone-2-sulfonate (AQ2S) and anthraquinone-2,7-disulfonate (AQ27S) further enhance the NO production over that produced in quinone-depleted sonicated solutions. In contrast, the hydrophobic quinones juglone (JQ) and 1,4-naphthoquinone (NQ) inhibit ultrasound-induced NO detection as compared to quinone-depleted solutions. Larger sonolytical decomposition of the hydrophobic quinones NQ and JQ, as compared to AQ2S and AQ27S, is detected which correlates with a larger production of pyrolysis-derived carbon-centered radicals. Reaction of those radicals with NO could explain NQ and JQ inhibition. This work suggests that sulfonated quinones could be used to enhance NO release from GSNO in tissues undergoing ultrasound irradiation.

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Toxicological testing of cytotoxic drugs (Review)

Cited by 22 publications

References 0 publications

Preclinical Toxicity, Toxicokinetics, and Antitumoral Efficacy Studies of DTS-201, a Tumor-Selective Peptidic Prodrug of Doxorubicin

Preclinical Toxicity, Toxicokinetics, and Antitumoral Efficacy Studies of DTS-201, a Tumor-Selective Peptidic Prodrug of Doxorubicin

Alkaline comet assay study with breast cancer patients: evaluation of baseline and chemotherapy-induced DNA damage in non-target cells

Quinone-enhanced sonochemical production of nitric oxide from s-nitrosoglutathione

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