Coadministration of swainsonine and doxorubicin attenuates doxorubicin-induced lethality in mice

This study in mice concerns the protective effectiveness and mechanisms of action by which a coadministered regimen of an immunomodulatory alkaloid swainsonine (8alphabeta-indolizidine-1alpha,2alpha,8beta-triol) protects against lethality induced by a single bolus intraperitoneal injection of LD50/14 doxorubicin. This swainsonine coadministration treatment regimen has been identified previously in our laboratory as the superior of the two optimal conditions for diminishing lethality in mice due to LD50/14 doxorubicin. The anthracycline, doxorubicin is a potent and widely used cancer chemotherapeutic agent whose clinical usefulness is limited by both a dose- and time-dependent cardiomyopathy. Specifically, mice were given simultaneous injections of swainsonine or its diluent buffer, phosphate buffered saline and LD50/14 doxorubicin on day 0, followed by twice daily injections of swainsonine or phosphate buffered saline up to day +9. The survival and well being of mice were monitored daily for 70 days, which may be considered equivalent to a period of 4 to 5 years in humans. This duration has a clinical implication with respect to the late manifestation of cardiotoxicity after doxorubicin treatment. We quantified the bone marrow cellularity of mice and performed in vitro progenitor cell assays to determine the effects of swainsonine coadministration treatment regimen on bone marrow competence after doxorubicin treatment. The effects of this regimen on doxorubicin-induced changes in heart morphology and on hematologic toxicities caused by doxorubicin were determined. This swainsonine coadministration treatment regimen significantly diminished doxorubicin-induced lethality and prolonged survival and well being of mice by preventing bone marrow pancytopenia from the start of therapy. It decreased bone marrow toxicity and facilitated its restoration. It accelerated restoration of blood hematocrit and total leukocyte levels. Also it facilitated the proliferation and differentiation of bone marrow pluripotent stem cells along the different paths to progenitor lineages, and significantly preserved the mouse heart morphology. These underlying mechanisms of action for the protection by swainsonine coadministration strongly suggest a potential role for swainsonine in high dose chemotherapy with doxorubicin.