Transcript Slide 1

Chemotherapy Directed Toward Defective BRCA-1 and BRCA-2
Genes in Breast and Ovarian Cancers
(See Figure 12-40 and Sidebar 12.11, p. 520 Weinberg)
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Propositions:
Redundant DNA-repair mechanisms needed by both normal and
neoplastic cells to repair DNA lesions incurred normally during cell
division.
One type of DNA repair involves poly-ADP-ribose polymerase (PARP).
BRCA-1 and BRCA-2 have DNA repair functions as “Housekeeping genes”.
Normal cells can use BRCA-1 and BRCA-2 repair functions as well as PARP
repair mechanisms.
Breast and Ovarian cancer cells lacking BRCA-1 and BRCA-2 must rely on
the PARP repair option.
What happens if one inhibits the PARP repair function using PARP
inhibitors?
Filename: BRCA2Therapy.ppt
Figure 12-40 Weinberg
Cells lacking BRCA-2 (red line) are
killed off (2 log kill or 99% kill) at
10E-7 M (0.1 uM) anti-PARP drug
concentration. (The structure of
the inhibitor is not specified).
Cells with BRCA-2 repair (blue or
green lines) can survive almost
1,000-fold higher concentration
of anti-PARP agent (10E-4M or
100 uM) because they can use
BRCA-2 for DNA repair.