I. Fichtner et al., CHARACTERIZATION OF 4 DRUG-RESISTANT P388 SUBLINES - RESISTANCE SENSITIVITY IN-VIVO, RESISTANCE-MARKERS AND PROLIFERATION-MARKERS, IMMUNOGENICITY/, Anticancer research, 14(5A), 1994, pp. 1995-2003
It was the aim of this study to compare drug-rsistant sublines of the
murine P388 in relation to resistance markers, the resistant phenotype
and immunogenicity. Resistance to drugs either belonging to the MDR t
ype (Doxorubicin, Vincristine, Mitoxantrone) or to the non-MDR type (M
ethotrexate) was generated in vivo in order to mimic the clinical situ
ation. All resistant sublines expressed the mdr1 gene and the p-glycop
rotein determined on m-RNA level or immunohistochemically, while no ex
pression was registered in the parent P388. The rhodamine 123 fluoresc
ence as marker for the energy dependent drug efflux pump was decreased
only in the MDR-sublines, while the parent P388 and the Methotrexate-
resistant line retained 100% or 90% of the dye, respectively. This ind
icates that the rhodamine efflux is a more function-related marker for
MDR than the mdr1 gene and the pgp. The in vivo characterization of t
he sublines as regards their sensitivity to cytostatics revealed a cle
ar-cut cross-resistance to MDR drugs in the MDR-lines, while the Metho
trexate resistant subline was only cross-resistant to Cytarabine. In e
ach resistant subline collateral sensitivity to certain but different
cytostatics was observed. Experiments to overcome resistance by concom
itant treatment with the modulators Nifedipine, Verapamil, Cyclosporin
A and Chloroquin led to only limited success. The sublines P388/Mitox
, P388/Vinc and P388/MTX developed immunogenicity which was never regi
stered in the original P388. Vaccination with lethally irradiated drug
-resistant cells resulted in a substantial rejection of viable rumor c
ells of the same line. With the P388/Mitox and P388/Vinc also an overc
ross immunization was possible. This generation of immunogenicity as a
concomitant characteristic of resistance should be considered as ther
apeutic potential also in the treatment of clinical cancer.