Genotoxic classification of anticancer drugs

Matney, Thomas S.; Nguyen, Tot V.; Connor, Thomas H.; Theiss, Jeffrey C.; Dana, William J.

doi:10.1002/tcm.1770050502

Cited by 58 publications

(18 citation statements)

References 11 publications

(8 reference statements)

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“…Such data cannot be considered evidence of a mutagenic response in the Salmonella assay, but they could act as a stimulus for the conduct of eukaryotic mutation studies in the case of a chemical of unknown mutagenicity. The present data (Table I) are consistent with the findings of Matney et al [1985] who reported weak (< 2-fold) increases in mutation frequency in strains TA1538 or TA98 (up to 2,000 p,g/plate) and Gupta et al [1987] who observed etoposide to be nonmutagenic to strains TA98 and TAlOO (up to 800 pg/plate). The latter authors confirmed the inactivity of etoposide in a range of other prokaryotic assays.…”

Section: Salmonella Assayssupporting

confidence: 95%

potent clastogenicity of the human carcinogen etoposide to the mouse bone marrow and mouse lymphoma L5178Y cells: Comparison to salmonella responses

Ashby¹,

Tinwell²,

Glover³

et al. 1994

Environ and Mol Mutagen

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The suspect human carcinogen, etoposide, is known to be genotoxic, producing both gene and chromosomal mutations, probably by virtue of its ability to inhibit topoisomerase II activity. The present paper describes assays conducted using the Salmonella assay, the mouse lymphoma tk+/- assay (gene and chromosomal mutation analysis and molecular analysis of tk-/- mutants) and the mouse bone marrow micronucleus assay. Nonreproducible, weak, dose-related increases in mutation frequency in strain TA98 (but not TA1538 or TA1537) of Salmonella typhimurium were observed. Etoposide was highly mutagenic at the heterozygous thymidine kinase (tk+/-) locus of L5178Y mouse lymphoma cells at concentrations below 0.1 micrograms/ml. Mostly small colony mutants were induced, consistent with the potent clastogenicity also observed. Molecular analysis of mutants indicated that 83% and 92% of large and small colony mutants, respectively, had lost the entire target gene sequence. Chromosomally aberrant L5178Y cells were approximately 2 to 600-fold more prevalent than small tk-/- mutant colonies. This suggests that the viable target for etoposide-mediated clastogenesis in the selective assay is approximately one-fifth of chromosome 11b, itself being approximately one-fortieth of the mouse genome. An unusually potent response was observed for etoposide in the mouse bone marrow micronucleus assay (63.1 +/- 18 MPE/1,000 PE 24 hours after an oral dose of 1 mg/kg). The minimum detectable dose level in the assay was between 0.01 and 0.1 mg/kg. At dose levels between 1 and 15 mg/kg, an inverse dose response was observed. This reduction in assay response was not due to the small concommitant decrease in the incidence of polychromatic erythrocytes, a conclusion based on studies with N-methyl-N-nitrosourea. Animals sampled 48 hours after dosing with etoposide (10 mg/kg) had no polychromatic erythrocytes in the bone marrow. These observations for the micronucleus assay await explanation. The chemical structure of etoposide is displayed and discussed within the context of such strong mutagenic activity being associated with a nonelectrophilic agent.

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Section: Salmonella Assayssupporting

confidence: 95%

potent clastogenicity of the human carcinogen etoposide to the mouse bone marrow and mouse lymphoma L5178Y cells: Comparison to salmonella responses

Ashby¹,

Tinwell²,

Glover³

et al. 1994

Environ and Mol Mutagen

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“…The ability of drugs used in the treatment of cancer to be carcinogens themselves is well documented (31,47,76,120,124,180,186,203). Harrison (78) listed 30 antineoplastic drugs that induced mutagenicity in vitro or carcinogenicity in vivo in animal models.…”

Section: Safety Cabinets In Pharmacy and Medicinementioning

confidence: 99%

Biological safety cabinetry

Kruse¹,

Puckett²,

Richardson³

1991

Clin Microbiol Rev

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The biological safety cabinet is the one piece of laboratory and pharmacy equipment that provides protection for personnel, the product, and the environment. Through the history of laboratory-acquired infections from the earliest published case to the emergence of hepatitis B and AIDS, the need for health care worker protection is described. A brief description with design, construction, function, and production capabilities is provided for class I and class III safety cabinets. The development of the high-efficiency particulate air filter provided the impetus for clean room technology, from which evolved the class II laminar flow biological safety cabinet. The clean room concept was advanced when the horizontal airflow clean bench was manufactured; it became popular in pharmacies for preparing intravenous solutions because the product was protected. However, as with infectious microorganisms and laboratory workers, individual sensitization to antibiotics and the advent of hazardous antineoplastic agents changed the thinking of pharmacists and nurses, and they began to use the class II safety cabinet to prevent adverse personnel reactions to the drugs. How the class II safety cabinet became the mainstay in laboratories and pharmacies is described, and insight is provided into the formulation of National Sanitation Foundation standard number 49 and its revisions. The working operations of a class II cabinet are described, as are the variations of the four types with regard to design, function, air velocity profiles, and the use of toxins. The main certification procedures are explained, with examples of improper or incorrect certifications. The required levels of containment for microorganisms are given. Instructions for decontaminating the class II biological safety cabinet of infectious agents are provided; unfortunately, there is no method for decontaminating the cabinet of antineoplastic agents.

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“…This In recent years, chemotherapy has been used increasingly in the treatment of cancers. Many of the drugs that have been successful in the treatment of cancers have also been shown to have mutagenic and carcinogenic properties [Sieber and Adamson, 1975;Harris, 1976;Matney et al, 1985;Sorsa et al, 19851. Since a significant number of cancer patients who were treated with antllneoplastic develop secondary later in their lives [Rosner and Gmnwald, 1974;Sieber and Adarnson, 1975;Perm, 1976;Meadows et al, 1977;Coltman, 1982;Kyle, 1982; concern was intensified when several studies demonstrated increased levels of mutagens in the urine of oncology nurses by means of bacterial assays [Falck et al, 1979;Anderson et al, 1982;Bos et al, 1982;Nguyen et al, 19821, and when cytostatic drugs were detected in the urine of nurses who handled these agents [Hirst et al, 1984).…”

Section: Introductionmentioning

confidence: 98%

Comparison of three assays for genetic effects of antineoplastic drugs on cancer patients and their nurses

Krepinsky¹,

Bryant

Davison

et al. 1990

Environ and Mol Mutagen

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Three assays have been compared for their ability to detect genetic damage caused by antineoplastic drugs in cancer patients and possible damage in the nurses who administered these drugs. The assays were sister chromatid exchanges (SCE) and chromosomal aberrations in peripheral blood lymphocytes, and the Salmonella/mammalian microsome assay on urine. Three comparisons were made: 1) patients before versus after treatment; 2) the administering nurses immediately after their work period versus after a few days off that followed (work and off-work); 3) the exposed nurses versus other nurses who did not administer antineoplastic drugs (controls). The SCE assay detected the treatments in all eight patients from whom complete data were obtained, and was positive in two nurses with a long history of smoking. The Salmonella/mammalian microsome assay detected eight of ten treatments in patients but failed to detect smokers. Four of nine patients receiving treatment were detected by the analysis of chromosomal aberrations. The SCE assay did not distinguish between the work and off-work samples in either the exposed or control nurses. The exposed nurses, as a group, had slightly fewer SCEs than the controls due to the two smokers detected in the latter group. Chromosomal aberration was the only assay which showed significant difference between the two samples of the exposed nurses and, consequently, between the exposed and control nurses. These differences, however, arose primarily from a higher frequency of aberrations found among the exposed nurses in samples taken after a few days away from work, rather than at the end of their work period. There is no evidence that the increase was connected to occupational exposure.

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Genotoxic classification of anticancer drugs

Abstract: The effects of bacterial DNA excision repair on the mutagenic and lethal actions of 17 injectable anticancer drugs have been used to classify them into three levels of potential risk to medical personnel who are involved in their preparation and administration.

Cited by 58 publications

References 11 publications

potent clastogenicity of the human carcinogen etoposide to the mouse bone marrow and mouse lymphoma L5178Y cells: Comparison to salmonella responses

potent clastogenicity of the human carcinogen etoposide to the mouse bone marrow and mouse lymphoma L5178Y cells: Comparison to salmonella responses

Biological safety cabinetry

Comparison of three assays for genetic effects of antineoplastic drugs on cancer patients and their nurses

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