Anti-cancer drugs and their effect on the ubiquitin cycle

Doxorubicin, a topo-isomerase II inhibitor, is used for a wide variety of
cancers such as acute leukemia and (non-) Hodgkin's lymphoma. At present it is
unclear whether topo-isomerase inhibition is the only mode of action of these
drugs. We have found that anthracyclins, similar to the proteasome inhibitor
bortezomib, can have an effect on the ubiquitin cycle. Although the action of
the drugs is different, they both change the ubiquitin (Ub) modification of
histones. This modification is critical in processes like gene silencing, DNA
repair, chromatine packing and cell survival. We have already deciphered the
mechanism employed by proteasome inhibitors to de-ubiquitinate histones. How
doxorubicin is affecting H2 ubiquitination and the consequences for tumoour
therapy are unknown and will be studied here. Theoretically, these drugs would
also be very effective when used in combination.

1. To decipher the biological basis underlying the alterations in
ubiquitination of histones in response to anthracyclines and proteasome
inhibitors.
2. to find out whether the combined use of anthracyclines and proteasome
inhibitors has additive or synergistic activity on histone de-ubiquitination.
3. to correlate changes in histone ubiquitination with response to treatment

From patients with hematological malignancies the ubiquitination of histones
will be studied prior to and 4 hours after the administration of anthracyclines
and/or proteasome inhibitors. These results will be correlated with clinical
outcome (response to treatment and event-free survival).

The participating patients will be asked to donate 2 blood samples, directly
prior to and 4 hours after the administration of anthracyclines and/or
bortezomib. The blood will be collected from the already inserted intravenous
canula which is used for the chemotherapy. There is no direct benefit for the
patient but the burden and risks are minimal.
The healthy volunteers will only donate a baseline blood sample.