Biomedical Engineering Reference
In-Depth Information
somewhat increased tolerated dosage of OLV-DOX (over F-DOX) will
result in an enhanced antitumor activity. The liposomes used here
are cleared quickly by the RES of liver and spleen and to a lesser
extent by the bone marrow. Our studies suggest that the mechanism
of antitumor activity of OLV-DOX is complex, and presumably results
from exposure of tumor cells to drug leaking from circulating
liposomes and drug released from the RES. Obviously, drug leakage
from circulating liposomes is undesirable since it increases toxicity.
Regarding drug release from the RES, the clinical conditions most
likely to benefit from this approach are limited. This approach should
not work for treatment of solid tumors, as in most solid tumors drug
exposure in relation to dosage may be suboptimal. The OLV-DOX
will be highly sensitive to factors such as RES/liver function, site of
tumor involvement, and proximity of tumor cells to RES cells.
The failure of our OLV-DOX approach in humans has some
basic “take home messages” that if used right should lead us to the
development of a liposomal doxorubicin formulation that should
be less toxic and more efficacious than free DOX in humans. This
failure served as the main driving force and as the basis for Doxil
®
development.
12.4 Doxil
®
Development
12.4.1
Turning DOX-OLV Failure into Doxil Success
We started our clinical trial of OLV-DOX in 1985. In summer of 1985
after we already had treated two patients, I started my sabbatical
at Liposome Technology Inc. (LTI) at Menlo Park. That year LTI also
licensed from Yissum two pending patent applications of Barenholz
and Gabizon on OLV-DOX (Barenholz and Gabizon, 1990, 1991).
One year later, LTI staff became involved in the OLV-DOX clinical
trial and expanded it to include, in addition to Israel, also the United
Kingdom. The UK studies were led locally by Roger New (Amselem
et al., 1992). This trial expansion allowed us to increase patient
number. By 1987 it became evident to us that this specific OLV-DOX
formulation would not become a viable product and is not good
enough for further development. We decided to exploit the results
of this study to bring us closer to understand the requirements for
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