Liposomal
drug delivery appears to improve the antitumor effect and reduce toxicity compared with the free
drug. The therapeutic index may be improved further by combining cytotoxic drugs and
radiotherapy. Successful therapy requires that the
cytotoxic agents reach the
tumor cells. Therefore, we studied
tumor growth and the microdistribution of
liposomal doxorubicin (
Caelyx) with and without additional ionizing radiation in human
osteosarcoma xenografts in athymic mice.
Caelyx was injected i.v. 1 day before single or fractionated
radiotherapy. Both chemoirradiation regimens induced significant
tumor growth delays and worked synergistically. Confocal
laser scanning microscopy showed that intact
liposomes were located in close proximity to endothelial cells, and the distribution of released
doxorubicin was heterogeneous. Before
radiotherapy, hardly any
doxorubicin was localized in the central parts of the
tumor.
Radiotherapy increased the
tumor uptake of
doxorubicin by
a factor of two to four, with
drug being redistributed farther from the vessels in the
tumor periphery and located around vessels in the central parts of the
tumor. Colocalization of
doxorubicin and hypoxic cells showed no distribution of
drug into hypoxic areas. Dynamic contrast-enhanced magnetic resonance imaging (MRI) 1 day before the injection of
Caelyx and 2 days
after treatment start showed that the combined treatment reduced the vascular volume and the vascular transfer rate of the MRI tracer. The results show that chemoirradiation with
Caelyx induces synergistic treatment effects. Improved intratumoral
drug uptake and distribution are responsible to some extent for the enhanced antitumor effect.