These talks were part of a symposium hosted by Dr. Dewhirst at Duke.
Timo L.M. ten Hagen, PhD
Laboratory Experimental Surgical Oncology
Department of Surgery
Rotterdam, the Netherlands
“Manipulation of Tumor Response with Vaso-active Agents”
The problem is poor perfusion in regions with viable tumor. This causes both hypoxia and poor drug delivery.
Isolated limb profusion with high dose melphalan, TNF or other vasoactive drugs was the strategy used. Hyperthermia may also be used. Used in both melanoma and sarcoma of the extremities.
TNF, Histamine, IL-2, hyperthermia, and MMP antagonists (matrix metalloproteases) all act on tumor vasculature. At this time he showed images of a TNF treated patient with a lower extremity sarcoma, with normalization of the angiogram. TNF alone doesn't seem to cause any regression on its own, but in combination with melphalan, an additional effect on tumor is seen in animal models. Interestingly, interstitial pressure is not significantly changed.
Addition of Melfalan + TNF or doxorubcin +TNF one sees an improvement in drug accumulation in tumor. Distribution is also more homogeneous. In either TNF or histamine hemorrhage is also seen in the tumor specimens (increasing the vascular permeability?).
One problem is that chemotherapy agents such as melphalan, even with isolated perfusion, pharmacokinetics remain poor. Efforts now directed towards liposomal drugs.
TNF + doxil (liposomal doxorubicin) resulted in an increase in tumor response rate, as well as growth delay. In normal tissues, concentrations were low, except for the spleen (TNF may be activating macrophages in this organ). 100nm liposomes seem to give the best localization into tumor.
Side note – it is fortunately easy to image doxorubicin because it fluoresces. One can use liposomes labeled with DIO to demonstrate differential concentrations of the intact liposomes and free doxorubicin. One issue is that many liposomes hold onto their doxorubicin, and the drug is not release to the target – the nucleus. (Can Res 2007)
TNF is also a toxic systemic agent, also termed cachectin due to it's role in cancer associated cachexia. At high doses it can lead to hypotensive shock and multi-system organ failure.
The second talk of the day was:
Lars Lindner, PhD
Department of Internal Medicine III
University Hospital Grosshadern
“Title: Potential of phosphatidyloligoglycerols in temperature sensitive liposomes”
Temperature sensitive liposomes are engineered to release contents at mild hyperthermic temperatures 40degrees.
Two Strategies for delivery
Interstitial drug release: Specificity controlled by increased vascular permeability in tumors, and which can be improved by the application of targeted heat. The cons to this approach include inefficient entrapment process, and high systemic drug load due to uptake by the reticular endothelial system (RES). In this approach, there is no need for quick drug release as the drug is within the interstitial compartment.
Intravascular drug release: has the potential to have a 100% drug delivery to the tumor region, however systemic recirculation is a limitation of this approach. It is important to have efficient drug release in this setting to maximize the targeting.
Phosphatidyloligoglycerols: three subtypes, and with PG2 and PG3 there are much more linear pharmacokinetics. By increasing the concentrations of PG2 and PG3, one can increase the rate of release with increase in temperature. These are development currently awaiting clinical applications.