Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00249 (Mutagen)
 5,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe in this paper cell survival studies, using in vitro clonogenic assays, performed on the B16 melanoma treated in situ with various cytotoxic agents. In addition we have determined the effects of these agents on the yield of cells obtained by trypsinization. In untreated tumours the mean cell yield was approximately 10(8)/g, which is 20--30% of the cells actually present in the tissue. The plating efficiency was approximately 40%. Most agents rapidly affected both cell yield and cell survival. For example, within 20--30 h, gamma-radiation and several alkylating agents reduced cell yield by about 40%. The cell yield change was associated with an increase in mean cell size. Cell yield was reduced even more (approximately 70%) by Vinca alkaloids. This large reduction was associated with extensive cell lysis, observed as an increase in the necrotic fraction of tumours from approximately 35% to approximately 70%. Adriamycin, bleomycin and Ara-C also produced a moderate reduction in cell yield (approximately 40%), but actinomycin D did not reduce cell yield and FU increased it by about 30%. Only gamma-radiation, cyclophosphamide, CCNU, BCNU and melphalan produced more than a 90% reduction in cell survival, although there was a small but measurable reduction with all other agents except vinblastine, HN2 and actinomycin D.
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PMID:Cell yield and cell survival following chemotherapy of the B16 melanoma. 72 48

Fifty-four newly diagnosed patients with advanced Hodgkin's disease were randomized between two alternating non cross-resistant chemotherapies: MOPP-ABVD (MOPP: Mustine, Vincristine, Procarbazine, Prednisone-ABVD: Adriamycin, Bleomycin, Vinblastine, Dacarbazine) and MOPP-ABVD-CEM (CEM: Carmustine, Etoposide, methyl-GAG). There were no significant differences between the two therapies as far as complete remission, survival, relapse free survival and toxicity were concerned. This study does not support the use of MOPP-ABVD-CEM for improving the long-term outcome of patients with advanced Hodgkin's disease.
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PMID:A prospective randomized study of two alternating, non cross-resistant chemotherapies for advanced Hodgkin's disease. 138 56

To evaluate a possible relationship of maternal exposure to anticancer drugs during the preimplantation period to blastopathies and postimplantation embryotoxicity, CD female rats were injected intraperitoneally on day 3 of pregnancy with 15 and 30 mg/kg of cyclophosphamide (CPA), 2 and 4 mg/kg of Adriamycin (ADR), 3 and 6 mg/kg of cis-platinum (Cis-Pt), or with 5 ml/kg of saline. Blastocysts were collected on day 5 of gestation and evaluated for gross morphology, cell number, and micronuclei. Some females were sacrificed on day 21 of pregnancy in order to evaluate postimplantation embryotoxicity. A reduction in cell number/blastocyst was observed only in animals exposed to Cis-Pt 6 mg/kg; vice versa, a dose-related increase of micronuclei and of blastocysts with micronuclei was found in all groups treated with the anticancer agents. A significant increase of postimplantation loss was recorded in the groups treated with high doses of Cis-Pt and ADR, but no clear signs of teratogenicity were observed.
Teratog Carcinog Mutagen 1990
PMID:Induction of micronuclei and toxic effects in embryos of pregnant rats treated before implantation with anticancer drugs: cyclophosphamide, cis-platinum, adriamycin. 198 52

His+ reversion at multiple his- loci, 8-azaguanine resistance, and a previously reported direct plating cytotoxicity test were used to measure the genotoxic potencies of a series of anthracycline derivatives in Salmonella typhimurium. N-demethylated amino sugar monosaccharide anthracyclines reverted most his- tester strains and were positive with 8-azaguanine selection. Reversion of strain TA98 was the most sensitive end point for measuring the mutagenic activity of the N-demethylated anthracyclines. N,N-dimethyl amino sugar derivatives of Adriamycin and daunomycin were negative as measured by His+ reversion in tester strain TA98, but generated positive responses in tester strain TA102 that were equal to or greater than those of the demethylated parent compounds. Similarly, N,N-dimethyl amino sugar derivatives of pyrromycinone and 1-deoxypyrromycinone had no mutagenic activity as measured by His+ reversion except in tester strains TA102 and TA104. These later compounds also gave positive responses with 8-azaguanine selection. In view of these results, the importance of amino sugar dialkylation and anthracycline mechanisms of mutagenesis are discussed.
Teratog Carcinog Mutagen 1986
PMID:Mutagenic and cytotoxic potencies of a series of anthracycline derivatives as measured by His+ reversion, 8-azaguanine resistance and direct plating cytotoxicity tests in Salmonella typhimurium. 287 34

The effects of excision repair and presence of plasmid pKM101 on the mutagenicities and cytotoxicities of the anthracycline derivatives Adriamycin, daunomycin, carminomycin, and 4-demethoxydoxorubicin were examined in strains of Salmonella typhimurium. Plasmid pKM101 has been shown to mediate inducible error-prone repair in S. typhimurium. While the test compounds were shown to produce a range of mutational responses in excision repair defective (uvrB-), pKM101-bearing strains of different his- backgrounds, proficiency in excision repair generally resulted in the elimination of mutagenic responses in all such strains except those that contain the hisG428 site. In the absence of pKM101, only hisD3052 uvrB- strain TA1538 was shown to be sensitive to anthracycline mutagenicity. A suspension (preincubation) test as well as a direct plating test showed that while proficiency in either excision repair (uvr+) or plasmid pKM101 error-prone repair afforded cellular protection against anthracycline cytotoxicity, plasmid-free uvrB- strains were most sensitive to anthracycline cytotoxicity.
Environ Mutagen 1986
PMID:Effects of excision repair and plasmid pKM101 on mutagenic and cytotoxic potencies of anthracycline derivatives in test strains of Salmonella typhimurium. 353 70

Muc (mutagenesis: UV: chemical) genes of plasmid pKM101, along with the chromosomal gene recA are known to be important constituents for full expression of inducible error-prone DNA repair in Salmonella typhimurium. This study investigates the affects of muc+ pKM101 and three of its derivatives bearing muc- point mutations (pGW1, pGW16, and pGW21) on spontaneous as well as anthracycline-induced back mutation to histidine independence. Different base-substitution and frameshift his- tester strains of S typhimurium were treated with the anthracyclines daunomycin, Adriamycin, carminomycin, and 4-demethoxy-doxorubicin. In many cases the muc- plasmids did mediate dose-dependent anthracycline mutagenicity as measured by His+ reversion. In many of the his- strains, the presence of muc+ pKM101 or muc- plasmids also resulted in a concomitant elevation of spontaneous reversion patterns over those seen with the plasmid-free parent strains. As a result, the sensitivity of most strains to anthracycline mutagenicity (based on His+ revertants/spontaneous background/microgram anthracycline) was not enhanced by muc+ pKM101 or its muc- mutant derivatives. In contrast, the low incidence of spontaneous His+ reversion in strains of the hisD3052 series, along with the inherently greater sensitivities of these strains to anthracycline-induced reversion, demonstrate most dramatically the mutagenesis-enhancing effects of muc+ pKM101 and muc- plasmids. In these and other cases in which muc- plasmid effects on enhancement of strain sensitivity to mutagenesis or cytotoxicity are observed, the overall spectrum of enhancement is the following, in decreasing order: pKM101 greater than pGW16 greater than pGW1 greater than no plasmid approximately equal to pGW21. Possible correlations are drawn between muc- plasmid effects on anthracycline-induced mutagenesis and cytotoxicity.
Environ Mutagen 1987
PMID:Plasmid pKM101 muc(-)- and muc(+)-mediated anthracycline mutagenicity and cytotoxicity in Salmonella typhimurium. 355 56

The alkylating agents represent one of the most important classes of antitumor agents and play a major role in combination with other agents in the curative chemotherapy of selected human cancers. By repeatedly exposing cells to escalating doses of an alkylating agent, we have developed four human tumor cell lines which are relatively stably resistant to the drug with which the culture was treated. The response of these cell lines to a variety of alkylating agents was compared to the response of the parent cell lines to the same drug. The Raji/HN2 line was 7-fold resistant to nitrogen mustard and about 3-fold resistant to 4-hydroxyperoxycyclophosphamide, but it was not resistant to N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU), melphalan (MEL), busulfan, trimethyleneiminethiophosphoramide, 4-hydroperoxyifosfamide, or cisplatin [cis-diamminedichloroplatinum(II)] (CDDP). The Raji/BCNU line was 5.3-fold resistant to BCNU and 4-fold resistant to both MEL and CDDP. The Raji/CP line was 7-fold resistant to CDDP and 3-fold resistant to both nitrogen mustard and BCNU, but it was not resistant to busulfan, trimethyleneiminethiophosphoramide, or 4-hydroperoxyifosfamide. The SCC-25/CP line, which was 12-fold resistant to CDDP, was 5-fold resistant to MEL and 3-fold resistant to 4-hydroxyperoxycyclophosphamide. The SCC-25/CP line was almost 24-fold resistant to methotrexate after 30-min treatment and about 7-fold resistant to methotrexate after continuous treatment. None of the other cell lines was resistant to methotrexate. The survival of SCC-25 and SCC-25/CP cells exposed to several antineoplastic agents was examined over several logs of survival. The SCC-25/CP cells are highly resistant to CDDP; the ratio of the slopes of the survival curves (SCC-25/CP to SCC-25) of the two lines was 43. At survivals of 1%, resistance to MEL and BCNU became evident in the SCC-25/CP line. At survivals of 0.1%, resistance to mitomycin C and, to a lesser degree, to Adriamycin and vincristine was evident. It is more difficult to produce resistance to alkylating agents, even with extended selection pressure, than to other antineoplastic drugs such as antimetabolites and natural products. We found no evidence of pleiotropic resistance in any alkylating agent-resistant cell line. Our results suggest that a judicious choice of alkylating agents given in sequential or concurrent combination may be a rational treatment strategy with potential applications in the clinic.
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PMID:Alkylating agents: in vitro studies of cross-resistance patterns in human cell lines. 373 Oct 96

The YFF sperm assay, which is a quantification of the incidence of sperm with two fluorescent bodies (YFF = two fluorescent bodies), was performed to measure Y chromosomal nondisjunction. Three categories of human subjects were analyzed: 1) nonexposed, 2) exposed to antineoplastic agents - ie, chemo- and radiation therapy, and 3) dibromochloropropane (DBCP)-exposed. The nonexposed individuals demonstrated a relatively constant mean YFF value of 1.3%, which was consistent with historical controls in this laboratory and with the results of other investigators. Further, a one-way analysis of variance among the means of the control samples revealed no statistical differences either between these men or within each man's samples. The individuals exposed to antineoplastic agents showed a three- to four-fold increase in the incidence of YFF sperm three to six weeks after the initiation of exposure to Adriamycin and X-irradiation. The maximum percentages of YFF per 1,000 sperm for each individual in this exposed group was analyzed by Wilcoxon's distribution free rank sum test using a one-sided alternative. The exposed individuals' maximum YFF percentages were statistically significantly increased when compared to the maximum YFF values of the nonexposed controls. The individuals exposed to the nematocide DBCP also exhibited a statistically significant increase in the number of sperm containing two Y chromosomes as determined by chi-square analysis with one degree of freedom (P less than 0.01). Data presented herein show statistically significant increases in the incidence of double Y chromosomes as measured by the presence of YFF sperm following exposure to Adriamycin, X-irradiation, and DBCP. It is suggested that men who have a history of antineoplastic therapy could be evaluated for evidence of Y-Y nondisjunction with this method. In the event of an increased YFF sperm level, genetic counseling and amniocentesis should be made available to the spouse where pregnancy has occurred. Further, because this procedure measures gametic mutation, is relatively simple, and is noninvasive, it should be considered for inclusion as part of a battery of medical tests for monitoring industrial populations.
Teratog Carcinog Mutagen 1980
PMID:Analysis of human spermatozoa for Y chromosomal nondisjunction. 611 11

The dose-response for the induction of acentric chromosome fragments was determined in neuroblasts of the grasshopper embryo (Chortophaga viridifasciata De Geer, Orthoptera: Acrididae) exposed in vitro to four direct-acting chemical known to be mutagenic, clastogenic, and carcinogenic: 4-nitroquinoline-1-oxide (4NQO), N-methyl-N-nitro-N-nitrosoguanidine (MNNG), Adriamycin (ADM), and bleomycin (BLM). After a 1-hr exposure followed by a 3-hr recovery period (untreated cell cycle time is 4 hr), acentric fragments were observed at doses down to 1 microM 4NQO, 1.25 microM MNNG, and 0.125 microM ADM and BLM. After an 8-hr continuous exposure, acentric fragments were induced by 4NQO at a dose as low as 0.125 microM. These low concentrations also reduced the number of dividing cells. No chromosome aberrations or mitotic effects were observed in untreated embryos or in those exposed only to the solvent dimethyl sulfoxide. Because of the short cell cycle and the sensitivity of the neuroblast to the induction of acentric chromosome fragments by chemical clastogens, a minimum of time is needed to perform the test. From a comparison with the prominent clastogen test systems currently used, it is concluded that the grasshopper neuroblast test is the fastest and that it detects some agents that some systems do not. Grasshoppers have a worldwide distribution. If neuroblasts of other species prove to be as sensitive to mutagens as those of Chortophaga, investigators in many countries would have available a eukaryotic mutagen test system that is simple, fast, reproducible, and inexpensive.
Environ Mutagen 1982
PMID:Neuroblast of the grasshopper embryo as a new mutagen test system. II. Chromosome breakage induced by in vitro exposure of embryos to the direct-acting mutagens 4NQO, MNNG, adriamycin, and bleomycin. 617 85

The repair of DNA damage is closely related to cell cycle, in terms of both modulation of repairing ability throughout the cell cycle and perturbations in replication. We have studied the induction of Unscheduled DNA Synthesis (UDS) in human fibroblasts (MRC-5) by some chemotherapeutic agents, selected for their different mechanisms of action. To take into account the interaction between repair and replication systems, the experiments were performed in both proliferating and quiescent cultures; semiconservative DNA synthesis inhibition was examined by microphotometric measurements in the same autoradiographic preparations used for UDS analysis. Vincristine, methotrexate and 6-thioguanine induced no UDS. Adriamycin, actinomycin D, and, to a lesser extent, cyclophosphamide and thiotepa gave positive results only in proliferating cultures, whereas bleomycin was an effective inducer of UDS in quiescent cells, with weak UDS levels in proliferating ones. In all these cases, the combined analysis of UDS and semiconservative DNA synthesis inhibition proved to be of value in the assessment of interaction between drugs and DNA in proliferating cultures. The results of our experiments emphasize the importance of the cycling conditions in the cellular response to DNA damage.
Teratog Carcinog Mutagen 1983
PMID:DNA repair induction by cytostatic drugs in proliferating and quiescent MRC-5 cells. 619 63


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