Mutagenic properties of anticancer drugs

Ferguson, Lynnette R.

doi:10.1007/978-94-011-0677-1_10

Cited by 6 publications

(3 citation statements)

References 197 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Chemotherapy has its greatest impact when given as adjuvant treatment before and/or after radical local therapy (Pinedo & Giaccone, 1997). However, most of these antineoplastic drugs are themselves mutagenic and/ or carcinogenic (Marselos & Vainio, 1991;Ferguson, 1995;Ferguson & Denny, 1995;Ferguson & Pearson, 1996). In cancer treatment the primary aim is to kill the cancerous cells.…”

Section: Introductionmentioning

confidence: 99%

Cytogenetic risk assessment of etoposide from mouse bone marrow

Choudhury

Palo

Sahu

2004

J of Applied Toxicology

View full text Add to dashboard Cite

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

show abstract

Section: Introductionmentioning

confidence: 99%

Cytogenetic risk assessment of etoposide from mouse bone marrow

Choudhury

Palo

Sahu

2004

J of Applied Toxicology

View full text Add to dashboard Cite

show abstract

“…2,51 Unfortunately, even for the most widely used anticancer drugs, there are gaps in the literature that make it difficult to assess the relative mutagenic potential of different types of compound. 32 The present compound, Et 2 SnCl 2 ÁL 4 , shows ability in blocking cell proliferation, which is a positive effect of several anticancer drugs. 52 Moreover, being structurally similar to cisplatin, it is expected that the mode of action of the tin complexes could be similar to that of cisplatin 2 .…”

Section: Mutagenicity Testsmentioning

confidence: 85%

“…31 Although most of the anticancer drugs currently in the clinic are effective in causing chromosomal damage, there is considerable variability in their ability to induce SCE. 32 For many of the alkylating agents, including cisplatin, SCE does indeed occur at lower concentrations and appears to be a more sensitive assay than direct measurement of chromosome aberrations. 33 The present study in vivo shows that exogenous addition of Et 2 SnCl 2 ÁL 4 induces SCEs and delay in cell-cycle kinetics in mouse bone-marrow cells.…”

Section: Mutagenicity Testsmentioning

confidence: 99%

Synthesis and characterization of diorganotin(IV) complexes ofN-(2-pyridylmethylene)arylamines and mutagenicity testingin vivo of Et2SnCl2�[L4=N-(2-pyridylmethylene)-4-toluidine]

Baul

Rivarola

et al. 1998

Appl. Organometal. Chem.

View full text Add to dashboard Cite

Diorganotin(IV) dichloride complexes of the type R2SnCl2·L (R = methyl, ethyl, vinyl, t‐butyl, n‐butyl or phenyl; L = N‐(2‐pyridylmethylene)arylamine) have been synthesized and characterized on the basis of IR, NMR and 119Sn Mössbauer studies. Investigation of the complexes indicated that N‐(2‐pyridylmethylene)arylamines form distorted trans‐octahedral complexes with R2SnCl2 similar to the well‐known R2SnCl2·L. Cytogenetic toxicology testing has been performed for Et2SnCl2·L4 [L4 = N‐(2‐pyridylmethylene)‐4‐toluidine] in mouse bone‐marrow cells in vivo since such testing is a regulatory requirement before new drugs are released. This tin compound induced delay in cell‐cycle kinetics and sister chromatid exchanges (SCEs) significantly. The effect of Et2SnCl2·L4 was greater when endogenous glutathione (GSH) was depleted by buthionine sulphoximine (BSO). It seems that Et2SnCl2·L4 induces SCEs due to formation of adduct by binding on DNA which could interfere in DNA synthesis and cause delay in cell proliferation. Depletion of GSH could reduce the shielding effect of GSH on chromatin and allows more Et2SnCl2·L4 to bind on DNA. © 1998 John Wiley & Sons, Ltd.

show abstract

Etoposide‐induced cytogenotoxicity in mouse spermatogonia and its potential transmission

Palo

Sahu

Choudhury

2005

J of Applied Toxicology

View full text Add to dashboard Cite

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.

show abstract

Mutagenic properties of anticancer drugs

Cited by 6 publications

References 197 publications

Cytogenetic risk assessment of etoposide from mouse bone marrow

Cytogenetic risk assessment of etoposide from mouse bone marrow

Synthesis and characterization of diorganotin(IV) complexes ofN-(2-pyridylmethylene)arylamines and mutagenicity testingin vivo of Et2SnCl2�[L4=N-(2-pyridylmethylene)-4-toluidine]

Etoposide‐induced cytogenotoxicity in mouse spermatogonia and its potential transmission

Contact Info

Product

Resources

About