In vitro analysis of BCNU-sensitivity in human malignant gliomas
I. A model study with alkylating, cross-linking and carbamoylating agents in anaplastic astrocytomas of pediatric age
Corresponding Author
Massimo A. Gerosa
Departments of Neurosurgery, University of Padova, Italy
Massimo A. Gerosa M.D. Department of Neurosurgery University of Verona Ospedale Geriatrico Via Mameli 37100 Verona ItalySearch for more papers by this authorMark L. Rosenblum
Brain Tumor Research Center, University of California San Francisco, USA
Search for more papers by this authorVincenzo Della Corte
Department of Neurosurgery, University of Padova, Italy
Search for more papers by this authorClaudio Licata
Departments of Neurosurgery, University of Padova, Italy
Search for more papers by this authorAlbino Bricolo
Departments of Neurosurgery, University of Padova, Italy
Search for more papers by this authorCorresponding Author
Massimo A. Gerosa
Departments of Neurosurgery, University of Padova, Italy
Massimo A. Gerosa M.D. Department of Neurosurgery University of Verona Ospedale Geriatrico Via Mameli 37100 Verona ItalySearch for more papers by this authorMark L. Rosenblum
Brain Tumor Research Center, University of California San Francisco, USA
Search for more papers by this authorVincenzo Della Corte
Department of Neurosurgery, University of Padova, Italy
Search for more papers by this authorClaudio Licata
Departments of Neurosurgery, University of Padova, Italy
Search for more papers by this authorAlbino Bricolo
Departments of Neurosurgery, University of Padova, Italy
Search for more papers by this authorAbstract
ABSTRACT – Like all chloroethyl-nitrosoureas of major clinical use, 1,3 bis-(2-chloroethyl)-l-nitrosourea (BCNU) – which is one of the most effective chem-otherapeutic agents for CNS malignancies – biologically degrades into active alkylating and carbamoylating moieties. Using a human brain tumor stem cell assay, we analyzed a series of anaplastic astrocytomas of pediatric age, characterized by different degrees of BCNU-resistance.
Early (2–4) passage cultures from these tumors were treated in vitro with model drugs for alkylation (BCNU, CHLZ (2-[3-(2-chloroethyl)-3-nitrosoureido]-2-deoxy-D-glucopyranose), ENU (N-ethyl-N-nitrosourea), cross-linking (BCNU, CHLZ) and carbamoylation BHCNU (1,3 bis (trans-4-hydrocyclohexyl)-l-nitrosourea): dose-schedules were compatible with clinically achievable levels.
Results of chemosensitivity tests confirmed that – as previously reported in malignant gliomas of the adult – cellular resistance to BCNU was closely related to the cross-linking activity of alkylating species. However, in pediatric gliomas the levels of cell kill after treatment with the purely carbamoylating agent BHCNU, even at the highest doses tested, were lower than expected.
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