We have previously developed a daunorubicin resistant subline of Ehrlich ascites carcinoma (EA/DR) for studies on the reversal of daunorubicin resistance. The mean survival of untreated BALB/c mice bearing drug sensitive parental tumour (EA/DS) is 18.4 +/- 0.6 days, mice bearing EA/DS treated with five daily doses of 0.3 mg kg-1 daunorubicin greater than 60 days, and mice bearing EA/DR treated with the same daunorubicin regimen, 21.1 +/- 1.4 days. We now report complete reversal of daunorubicin resistance in EA/DR by cyclosporin A (CsA). The in vitro daunorubicin IC50, defined as that concentration of daunorubicin required to inhibit 50% of DNA synthesis, in EA/DR was 6.7 +/- 1.15 micrograms ml-1 compared to 2.8 +/- 0.72 micrograms ml-1 in EA/DS. This value was reduced to 2.8 +/- 0.52 and 2.1 +/- 0.10 micrograms ml-1 daunorubicin by 3.3 and 13.2 micrograms ml-1 CsA respectively, P less than 0.05. The MST of groups of host mice bearing EA/DR either untreated, treated with five daily doses of 0.3 mg kg-1 daunorubicin, treated with 80 mg kg-1 CsA in five divided daily doses or treated with combined daunorubicin-CsA were 19.0 +/- 1.0, 21.1 +/- 1.4, 24.0 +/- 2.6 and greater than 60 days respectively. The mean survival of groups of host mice bearing EA/DR treated with 5 mg kg-1 or 10 mg kg-1 CsA simultaneously with daunorubicin for five days was also greater than 60 days. These differences are highly significant.

Cyclosporin A (CsA) is an effective modulator of multidrug resistance (MDR) in vitro and in murine tumour systems in vivo. We now report the production of immunity to L1210 leukaemia by the addition of CsA to VP-16 therapy of leukaemic BDF/1 mice. VP-16/cyclosporin A tumour immunity induction arises as a consequence of active therapy independently of immunisation with modified tumour cells. The addition of CsA to VP-16 prolongs survival of BDF/1 host mice bearing L1210 leukaemia beyond that produced by equivalent dose VP-16 alone. A subpopulation of 60-day surviving mice after combined VP-16/CsA are immune to rechallenge with the same leukaemia inoculum to which they were originally exposed. Spleen cells from immune mice adoptively transfer anti-L1210 leukaemia immunity to untreated BDF/1 mice in a dose dependent, statistically significant manner. Adoptive transfer experiments additionally suggest active recruitment of immunologic response in recipient animals: (1) We have been able to perpetuate leukaemia immunity in four sequential cohorts of naive recipient mice. This propogation of adoptive immunity is accomplished by use of spleen cells harvested from each preceeding passively-protected animal cohort; (2) Cyclophosphamide pretreatment of adoptive transfer recipient mice abrogates the ability of their splenocytes to perpetuate passive protection in sequential adoptive transfer experiments.

Purpose: Idazoxan hydrochloride (IDA) is a 241 molecular weight imidazoline and adrenoreceptor ligand. It binds to mitochondrial membranes and promotes apoptosis of pancreatic beta cells. Since IDA has not been tested against tumor cells, the purpose of our study was to determine if IDA has antineoplastic activity. Methods: We used the conversion of a soluble tetrazolium salt to an insoluble formazan precipitate and differential staining cytotoxicity assays to determine if IDA was cytotoxic to cell lines of murine lung cancer and human prostate cancer, as well as to a variety of fresh human tumor samples. We used flow cytometry to analyze cell death and calreticulin expression. Results: IDA is cytotoxic to both cell lines and against aliquots of specimens of breast, gastric, lung, ovarian and prostate cancers as well as non-Hodgkin's lymphoma. It produces apoptotic cell death and promotes calreticulin expression, suggesting that IDA might be immunomodulatory in vivo. Conclusion: We anticipate that IDA will be clinically useful in cancer treatment. © 2009 The Author(s).