Chemistry Reference
In-Depth Information
fludarabine/Ara-C/idarubicin,
45
Ara-C/mitoxantrone,
46
Ara-C/G-CSF,
47
and
hydroxyurea/azacitidine.
48
The most significant study is a comparison of daunorubicin (45mgm
2
on
days 1, 2, and 3) and cytarabine (100mgm
2
on days 1 through 7), with or
without gemtuzumab ozogamicin (at a reduced dose of 6mgm
2
on day 4). A
CR rate of 84% with gemtuzumab ozogamicin vs. 55% without has been seen
so far. This combination with gemtuzumab ozogamicin has been well tolerated
with no incidence of VOD. At 6 months the median duration of CR had not
been reached.
18
Combinations have also been used in pediatric AML.
49
5.8 Mechanistic Studies
Several laboratory support studies have been performed to help define the
parameters for response and resistance for gemtuzumab ozogamicin. The role
of CD33 is the most important of these parameters. Although CD33 expression
does correlate with response,
50
the correlation is not as strong as might be
expected. Indeed, there is evidence that response can be seen with no CD33 in
cells that have high endocytic capacity.
51
It has also been shown that excessive
levels of CD33 in circulation diminish response, presumably due to the di-
culty of overcoming this antigen sink and accessing the sites of leukemia in the
bone marrow.
52
Fortunately, polymorphisms in CD33 appear to have no effect
on the response to gemtuzumab ozogamicin.
53
Inherent sensitivity to calicheamicin is another obvious possible parameter
that has been explored.
54
A 100 000-fold difference in sensitivity between the
most- and least-sensitive bone marrow samples was seen. Some of this differ-
ence has been shown to be due to P-glycoprotein-mediated drug resistance.
55
Several attempts have been made both in laboratory studies and in clinical
trials to overcome resistance,
56,57
but practical success will require further
clinical work.
44
Other resistance mechanisms have been explored. BCRP
58
and MRP2 do not
confer resistance but MRP1 does.
55
As expected, apoptosis related pathways
have been shown to be important, specifically Bak/Bax,
59
mitochondrial
apoptotic pathways activated by PK11195,
57
and low levels of Chk1 and Chk2
phosphorylation.
60
Syk down-regulation has also been shown to correlate with
resistance.
61
5.9 Summary and Future Prospects
Gemtuzumab ozogamicin is still the first and only antibody-directed che-
motherapeutic agent approved for use. The research that led to this agent was
critical in the conjugate field in making some key observations. It was the first
conjugate to show that modifying the structure of the cytotoxic agent, in this
case by going from g-calicheamicin conjugates to N-acetyl-g- conjugates, can
lead to a significant improvement in the therapeutic window in preclinical in
vivo models. It and the calicheamicin conjugate CMB-401, which was being
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