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Modulation of cyclophosphamide activity by O 6-alkylguanine-DNA alkyltransferase (1999)

Friedman, Henry S. ; Pegg, Anthony E. ; Johnson, Stewart P. ; [et al.]

Springer

Cancer chemotherapy and pharmacology 43 (1999), S. 80-85

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ISSN: 1432-0843

Keywords: Key words Alkylating agents ; Antineoplastic agents ; Cyclophosphamide ; Drug resistance ; Nitrogen mustard compounds

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Purpose: The human medulloblastoma cell line D283 Med (4-HCR), a line resistant to 4-hydroperoxycyclophosphamide (4-HC), displays enhanced␣repair of DNA interstrand crosslinks induced by phosphoramide mustard. D283 Med (4-HCR) cells are cross-resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea, but partial sensitivity is restored after elevated levels of O 6-alkylguanine-DNA alkyltransferase (AGT) are depleted by O 6-benzylguanine (O 6-BG). Studies were conducted to define the activity of 4-HC and 4-hydroperoxydidechlorocyclophosphamide against D283 Med (4-HCR) after AGT is depleted by O 6-BG. Methods: Limiting dilution and xenograft studies were conducted to define the activity of 4-HC and 4-hydroperoxydidechlorocyclophosphamide with or without O 6-BG. Results: The activity of 4-HC and 4-hydroperoxydidechlorocyclophosphamide against D283 Med (4-HCR) was increased after AGT depletion by O 6-BG preincubation. Similar studies with Chinese hamster ovary cells, with or without stable transfection with a plasmid expressing the human AGT protein, revealed that the AGT-expressing cells were significantly less sensitive to 4-HC and 4-hydroperoxydidechlorocyclophosphamide. Reaction of DNA with 4-HC, phosphoramide mustard, or acrolein revealed that only 4-HC and acrolein caused a decrease in AGT levels. Conclusions: We propose that a small but potentially significant part of the cellular toxicity of cyclophosphamide in these cells is due to acrolein, and that this toxicity is abrogated by removal of the acrolein adduct from DNA by AGT.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002800050866

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Controlled release of 4-hydroperoxycyclophosphamide from the fatty acid dimer-sebacic acid copolymer (1992)

Buahin, Kwame G. ; Judy, Kevin D. ; Hartke, Carol ; [et al.]

New York, NY : Wiley-Blackwell

Polymers for Advanced Technologies 3 (1992), S. 311-316

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ISSN: 1042-7147

Keywords: Controlled release ; Polymeric release ; Drug delivery ; Malignant glioma ; Cyclophosphamide ; Chemistry ; Polymer and Materials Science

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics

Notes: Controlled polymeric release of chemotherapeutic agents has shown promise in the management of malignant gliomas. 4-Hydroperoxycyclophosphamide (4HC), loaded on the fatty acid dimer-sebacic acid copolymer (FAD:SA, 1:1), significantly prolonged survival in rats implanted with F98 and 9L gliomas. Here, we studied the in vitro and in vivo release kinetics in phosphate-buffered saline and rat brain of 20% 4HC/FAD:SA (wt:wt), the optimal dose for treatment of rat gliomas. In vitro release under infinite sink conditions was steady over the initial 12 hr to a peak of 20-35% of impregnated drug, consistent with early phase control via surface erosion. Release over the next 3 weeks was minimal, consistent with barrier formation around the polymer by an oily fatty acid dimer degradation product and consequent slowing of release. However, the polymer started to disintegrate by day 4, and there were minimal visible remnants by 3 weeks. Thus, a considerable amount of polymer-carried drug was probably lost in the disintegrating fragments. Also, drug loss is expected from its inherent hydrolytic instability. In vivo release into brain revealed two peak levels of drug at 0-1 hr and 5-20 days. With loaded polymer implanted intraperitoneally or cyclophosphamide injected systemically, peak brain drug levels were measured in 2-8 hr, with substantial decrease by 48 hr without a second peak. Brain levels were substantially higher than blood levels at all time periods. We conclude that FAD:SA (1:1) adequately protects the otherwise labile 4HC, allowing effective and substained drug release in vivo. Furthermore, it should be possible to modify the polymer to adjust the time of peak release for more beneficial therapeutic effects.

Additional Material: 6 Ill.