THE ANTINEOPLASTIC DRUG PACLITAXEL HAS IMMUNOSUPPRESSIVE PROPERTIES THAT CAN EFFECTIVELY PROMOTE ALLOGRAFT SURVIVAL IN A RAT HEART TRANSPLANT MODEL1

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Abstract
Recurrent and de novo neoplasms are ominous risk factors for transplant patients. In particular, when organ transplantation is attempted to cure isolated cancers, conventional immunosuppression likely promotes cancer reestablishment. Therefore, drugs with both immunosuppressive and antineoplastic activity are needed. We show that the anticancer agent paclitaxel may fulfill these diverse expectations. Heterotopic heart transplantation was performed in the ACI-to-Lewis or Lewis-to-ACI rat-strain combination and paclitaxel was injected i.p. daily (days 0–14) at doses from 0.75–1.5 mg/kg. Serum cytotoxic antidonor antibody levels were measured using a complement-mediated cell cytotoxicity assay. In vitro, the effect of paclitaxel on Lewis lymphocyte viability and apoptosis was determined. Also, Lewis lymphocytes preconditioned with irradiated ACI cells±paclitaxel, were restimulated with ACI cells and tested for cytotoxic T cell (CTL) activity and interleukin-2 (IL-2) production. Paclitaxel promoted heart allograft survival in a dose-dependent manner in both high- and low-responder transplant combinations. Furthermore, low-doses of paclitaxel (0.75–1.0 mg/kg) and cyclosporine (1 mg/kg) in combination synergistically increased transplant survival. Immunologically, paclitaxel markedly reduced the antidonor cytotoxic antibody response. In vitro, nearly 90% of prestimulated lymphocytes were killed by paclitaxel and cells became positive for the apoptosis marker, annexin-V. Furthermore, paclitaxel reduced CTL activity and IL-2 production after alloantigen rechallenge. Paclitaxel, a clinically proven antineoplastic agent, also has potent immunosuppressive properties in rodent organ transplantation. This drug could be extremely valuable in transplant situations where de novo cancer develops, or when organ transplantation is performed to treat isolated, but typically recurrent, neoplasms.