Use of cyclophosphamide as a positive control in dominant lethal and micronucleus assays

Krishna, G.; Petrere, Judith A.; Anderson, John A.; Theiss, Jeffrey C.

doi:10.1016/0165-1161(95)00038-0

Cited by 32 publications

(18 citation statements)

References 17 publications

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“…The induction of significantly high percentages of aberrant metaphases, chromosomal aberrations (excluding gaps) and micronuclei per 1000 PCEs by CY (40 mg kg −1 body wt. of mice) in the present study is in complete agreement with its earlier reported clastogenic action in mouse bone marrow (Mohn & Ellenberger, 1976;Rohrborn & Basler, 1977;Machemer & Lorke, 1978;Mavournin et al, 1990;Anderson et al, 1995;Krishna et al, 1995). In the mitotic index study the induced percentage of dividing cells by CY did not differ significantly from that of the vehicle control group.…”

Section: Mitotic Index Studysupporting

confidence: 95%

Cytogenetic risk assessment of etoposide from mouse bone marrow

Choudhury

Palo

Sahu

2004

J of Applied Toxicology

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Increased clinical applications of the anticancer drug etoposide (a non-intercalative epipodophyllotoxin derivative) and the frequent induction of a second malignancy, particularly leukaemia, in post-etoposide-treated cancer survivors warrant detailed genotoxicity testing of etoposide. The genotoxicity test results available on etoposide are either primarily in in vitro test systems or in lower organisms after treatment with unusually high doses, or after chronic exposures, having little extrapolative value to humans. Therefore, a cytogenetic risk assessment study on etoposide in mouse in vivo was undertaken after a low dose (in accordance with the human therapeutic dose) single exposure. The cytogenetic toxicity of etoposide was assessed from bone marrow of mouse at three separate endpoints: chromosomal aberration and mitotic index studies at 24 h post-treatment and the micronucleus test (MNT) at 30 h post-treatment. The flame drying technique using colchicine, hypotonic sodium citrate, methanol-glacial acetic acid and Giemsa was followed for the preparation of slides for the metaphase chromosomal aberration and mitotic index studies and a simple technique was followed for the MNT. Although induction of chromosomal aberrations, excluding gaps, per 100 metaphases by 10 and 15 mg kg(-1) etoposide was not significant statistically, 20 mg kg(-1) of etoposide induced a significantly higher number of chromosomal aberrations in female (P < or = 0.01) and male (P < or = 0.05) mice. There was no significant change in the induced percentages of dividing cells by any of the doses of etoposide tested. The micronucleus induction also was not significant statistically with the lowest dose but it was significant in female (P

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Section: Mitotic Index Studysupporting

confidence: 95%

Cytogenetic risk assessment of etoposide from mouse bone marrow

Choudhury

Palo

Sahu

2004

J of Applied Toxicology

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“…To induce damage to spindle fibers and to chromosomes, we used colchicine and cyclophosphamide, compounds commonly used as positive controls for genotoxicity assays [Yamamoto and Kikuchi, 1980;Harper et al, 1989;Krishna et al, 1995]. The means, standard deviations, and significance of the PMNC frequencies from the different treatment groups are given in Table I.…”

Section: Resultsmentioning

confidence: 99%

Induction of micronuclei in proestrus vaginal cells from colchicine‐ and cyclophosphamide‐treated rats

Zúñiga‐González

Gómez‐Meda

Zamora‐Pérez

et al. 2003

Environ and Mol Mutagen

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“…Krishna et al (1995) has recommended its use as a positive control chemical in genotoxicity tests. In the present study, the cyclophosphamide-induced high percentage of aberrant spermatogonial metaphases, the high frequency of chromosomal aberrations excluding gaps (Table 1), the higher percentages of aberrant spermatocytes (Table 2) and the abnormal sperm (Table 3) are in complete agreement with earlier reports (Rathenberg, 1975;Wyrobek and Bruce, 1975;Generoso et al, 1978;Witt and Bishop, 1996).…”

Section: Discussionmentioning

confidence: 99%

Etoposide‐induced cytogenotoxicity in mouse spermatogonia and its potential transmission

Palo

Sahu

Choudhury

2005

J of Applied Toxicology

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As cancer chemotherapeutic agents are cytogenotoxic but not target-specific during systemic treatment, they affect all the encountered cells including the non-cancerous ones and consequently lead to the recurrence of second malignancy in post-chemotherapeutic cancer survivors. The effects would be persistent if the stem cells were affected. These drugs also may affect germline cells during therapeutic treatments. There is every chance that the effects are transmitted through the germline cells to the gametes and to the next generation if the gonadal mother cells are affected. Such transmission of effects from the post-chemotherapeutic childhood cancer survivors is of serious concern but very little attention has been given so far to such studies. Etoposide (VP-16)--a semi-synthetic epipodophyllotoxin derivative, a DNA non-intercalating agent and a topoisomerase II inhibitor--is prescribed frequently for the treatment of various types of cancers. It is a potent clastogen inducing chromosomal damage both in vitro and in vivo. Its clastogenic effect is indirect through inhibition of the catalytic activity of topoisomerase II enzymes, which maintain the topology of DNA during replication, recombination, transcription, etc. by forming a 'cleavable complex' and facilitate the cleaving and re-ligation of the cleaved DNA to relieve the torsional stress during such events. Transient stabilization of the cleavable complex by etoposide leads to illegitimate ligation of the cleaved DNA. Consequently, single- and double-strand breaks occur. In the present study, the clastogenic potential of three different doses of etoposide (10, 15 and 20 mg kg(-1)) in the male germline of mice was assessed from the dividing spermatogonia after a single exposure for one cell cycle duration at 24 h post-treatment. Transmission of such effects was assessed from the frequency of aberrant primary spermatocytes at week 4 post-treatment and of abnormal sperm at week 8 post-treatment. All three doses of etoposide were found to be clastogenic to the dividing spermatogonia of mice, and mostly chromatid breaks were induced. The effects also were transmitted through the male germline of mice, which was evident from the prevalence of statistically significant increased percentages of aberrant primary spermatocytes at week 4 posttreatment and the higher percentages of abnormal sperm at week 8 post-treatment. Thus, there is every chance that the cytogenotoxic effects of etoposide are transmitted to the next generation through the male germline of post-chemotherapeutic cancer survivors, therefore it is essential to make etoposide target-specific or modulate its effects.

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Use of cyclophosphamide as a positive control in dominant lethal and micronucleus assays

Cited by 32 publications

References 17 publications

Cytogenetic risk assessment of etoposide from mouse bone marrow

Cytogenetic risk assessment of etoposide from mouse bone marrow

Induction of micronuclei in proestrus vaginal cells from colchicine‐ and cyclophosphamide‐treated rats

Etoposide‐induced cytogenotoxicity in mouse spermatogonia and its potential transmission

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