Inhibition of the hepatic o6-alkylguanine-DNA alkyltransferase in vivo by pretreatment with antineoplastic agents

Meer, Lisa; Schold, S. Clifford; Kleihues, Paul

doi:10.1016/0006-2952(89)90282-7

Cited by 32 publications

(6 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The most recently developed of these radiotracers, butyl-2-methyl-malonic acid (ML-9; molecular weight, 173), has been applied to the study of apoptotic tumor cells in vitro and in vivo [66]. Despite improvement in tumor uptake in vitro and in vivo, the absolute uptake values, even in tumors treated with extremely high doses of chemotherapy (median lethal dose of intraperitoneal doxorubicin, 19.6 mg/kg [67]; carmustine [BCNU], 30 mg/kg [68,69]; 5-fluorouracil, 200 mg/kg [70]) spaced 48 hours apart, remain well below 1.5% injected dose/g and are seen only after observable decreases in tumor weight compared with control values. Supranormal doses of chemotherapeutic agents are known to induce necrosis rather than apoptosis, raising the question of the mechanisms of radiotracer localization in this study.…”

Section: Uncategorized Radiotracers For the Imaging Of Apoptosismentioning

confidence: 99%

Multimodality Molecular Imaging of Apoptosis in Oncology

Blankenberg

Norfray

2011

American Journal of Roentgenology

View full text Add to dashboard Cite

show abstract

Section: Uncategorized Radiotracers For the Imaging Of Apoptosismentioning

confidence: 99%

Multimodality Molecular Imaging of Apoptosis in Oncology

Blankenberg

Norfray

2011

American Journal of Roentgenology

View full text Add to dashboard Cite

show abstract

“…Another possible explanation for ATase loss is that there is a direct depleting effect on the ATase itself: as far as we are aware, 06-alkylguanine lesions have not yet been identified in DNA in vivo after administration of cyclophosphamide or its metabolites. There are two reports (Kleihues & Margison, 1976;Meer et al, 1989) which showed that cyclophosphamide is able to increase the amount of 06-methylguanine in DNA following a chasing dose of methylating agent in rodent liver and both authors attributed this to some as yet unidentified 06-alkylation product of guanine in DNA which is repaired by ATase and results in ATase depletion. Alternatively, there may be a direct reaction of the cyclophosphamide metabolite acrolein with ATase: when given systemically, cyclophosphamide is metabolised by the hepatic mixedfunction oxidases, to 4-hydroxycyclophosphamide, the 'transport' form which enters cells and eventually decomposes intracellularly to phosphoramide mustard, the ultimate crosslinking metabolite of cyclophosphamide, and acrolein (Brock, 1989;Sladek, 1987).…”

Section: Discussionmentioning

confidence: 99%

Cyclophosphamide decreases O6-alkylguanine-DNA alkyltransferase activity in peripheral lymphocytes of patients undergoing bone marrow transplantation

Lee

Crowther²,

Scarffe³

et al. 1992

Br J Cancer

View full text Add to dashboard Cite

Summary 06-alkylguanine-DNA-alkyltransferase (ATase) levels were measured in extracts of peripheral blood lymphocytes taken at various times during chemotherapy from 19 patients with various haematological malignancies. Seven patients with advanced Hodgkin's disease received preparative treatment consisting of cyclophosphamide (1.5 g m-2, daily) administered on days 1 to 4 and BCNU (600 mg m-2) on day 5 prior to autologous bone marrow rescue (ABMR) delivered on day 7. Treatment in the remaining 12 patients consisted of cyclophosphamide (1.8 g m2, daily) given on days 1 and 2 followed at day 4 with total body irradiation (TBI) administered in six fractions over the subsequent 3 days to a total dose of 1200 cGy prior to bone marrow transplantation. In the Hodgkin's group, significant decreases in ATase activity were seen during the cyclophosphamide treatment, and the median ATase nadir was 32% (range 0% to 57%) of pretreatment levels following 4 days of cyclophosphamide. In one patient, no ATase activity was detectable following the 4th cyclophosphamide treatment. ATase activities decreased further after BCNU administration to a median of 19% (range 0% to 32%) of pretreatment levels. Extensive cyclophosphamide-induced reduction of lymphocyte ATase levels was also seen in the other group of 12 patients treated with cyclophosphamide/TBI: postcyclophosphamide median ATase nadir was 35% (range 12% to 78%) of the pretreatment levels. No ATase depletion was seen when cyclophosphamide (up to 1O mM) was incubated for 2 h with pure recombinant human ATase in vitro whereas ATase activity was reduced by 90% on preincubation with 100 tsm acrolein or with > 1 mM phosphoramide mustard. This suggests that a cyclophosphamide-induced decrease in ATase levels in human peripheral lymphocytes in vivo may be due to depletion mediated by the production of intracellular acrolein. Since ATase appears to be a principal mechanism in cellular resistance to the cytotoxic effects of BCNU and related alkylating agents, these observations suggest that a cyclophosphamide-induced reduction in ATase activity may be an additional factor in the effectiveness of the combined sequential therapy.

show abstract

“…The correlation between O 6 -MT levels and the sensitivity to nitrosourea alkylating agents in tumor xenografts has led to interest in the potential of modulating O 6 -MT activity. Depletion of O 6 -MT activity has been obtained following treatment with dacarbazine, streptozotocin, temozolomide and procarbazine [52][53][54]. Data on O 6 -MT in ependymomas is sparse, but there is evidence that measurable levels are detectable in most tumors [55][56][57].…”

Section: Experimental Investigationsmentioning

confidence: 99%

The Role of Chemotherapy inNewly Diagnosed Ependymoma of Childhood

1998

View full text Add to dashboard Cite

The use of chemotherapy in treating children with newly diagnosed ependymoma is currently being investigated, both clinically and experimentally. Assessment of the true efficacy of this modality is hampered by a lack of prospective randomized trials comparing conventional treatment schemes of aggressive surgical excision followed by radiation therapy with or without addition of chemotherapy. Although with current regimens, the role of chemotherapy in newly diagnosed disease appears limited, measurable disease responses have been recognized. Preliminary studies support the potential use of chemotherapy in infants in an effort to delay radiation therapy or even avoid radiation therapy, although with conventional chemotherapy, a delay exceeding 12 months is inadvisable. Additionally, preliminary data suggest that in children with incompletely resected tumors, chemotherapy may be of benefit as an adjunct to second-look surgery. Experimental work investigating chemotherapeutic sensitivity, molecular genetics, or mechanisms to overcome drug resistance may offer some benefit in utilizing chemotherapy for ependymoma of childhood.

show abstract

Inhibition of the hepatic o6-alkylguanine-DNA alkyltransferase in vivo by pretreatment with antineoplastic agents

Cited by 32 publications

References 22 publications

Multimodality Molecular Imaging of Apoptosis in Oncology

Multimodality Molecular Imaging of Apoptosis in Oncology

Cyclophosphamide decreases O6-alkylguanine-DNA alkyltransferase activity in peripheral lymphocytes of patients undergoing bone marrow transplantation

The Role of Chemotherapy inNewly Diagnosed Ependymoma of Childhood

Contact Info

Product

Resources

About