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Vol. 60, Issue 6, 1268-1279, December 2001
Division of Cell and Molecular Biology, Department of Biology,
Boston University, Boston, Massachusetts
Cyclophosphamide (CPA), a widely used oxazaphosphorine anti-cancer
prodrug, is inactive until it is metabolized by cytochrome P450 to
yield phosphoramide mustard and acrolein, which alkylate DNA and
proteins, respectively. Tumor cells transduced with the human
cytochrome P450 gene CYP2B6 are greatly sensitized to
CPA, however, the pathway of CPA-induced cell death is unknown. The present study investigates the cytotoxic events induced by CPA in 9L
gliosarcoma cells retrovirally transduced with CYP2B6,
or induced in wild-type 9L cells treated with mafosfamide (MFA) or 4-hydroperoxyifosfamide (4OOH-IFA), chemically activated forms of CPA
and its isomer ifosfamide. CPA and MFA were both shown to effect tumor
cell death by stimulating apoptosis, as evidenced by the induction of
plasma membrane blebbing, DNA fragmentation, and cleavage of the
caspase 3 and caspase 7 substrate poly(ADP-ribose) polymerase (PARP) in
drug-treated cells. Caspase 9 was identified as the regulatory upstream
caspase activated in 9L cells treated with CPA, MFA, or 4OOH-IFA,
implicating the mitochondrial apoptotic pathway in
oxazaphosphorine-induced tumor cell death. Correspondingly, expression
of the mitochondrial proapoptotic factor Bax enhanced caspase 9 activation, plasma membrane blebbing, and drug-induced cytotoxicity.
Conversely, overexpression of the mitochondrial antiapoptotic factor
Bcl-2 blocked caspase 9 activation, leading to an inhibition of
drug-induced plasma membrane permeability and blebbing, terminal
deoxynucleotidyl transferase dUTP nick-end labeling positivity, PARP
cleavage, Annexin V positivity, and drug-induced cell death. Although
Bcl-2 thus blocked the cytotoxic effects of activated CPA, it did not
inhibit the drug's cytostatic effects. CPA induced S-phase cell cycle
arrest followed by conversion to an apoptotic pre-G1 state
in wild-type 9L cells; by contrast, Bcl-2-expressing 9L cells
accumulated in G2/M in response to CPA treatment.
Intratumoral expression of Bcl-2 and related family members, including
both apoptotic and antiapoptotic factors, is thus an important
determinant of the responsiveness of tumor cells to CPA and ifosfamide,
both in the context of conventional chemotherapy and in patients
sensitized to these oxazaphosphorine drugs by the use of cytochrome
P450-based gene therapy.
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