We demonstrate that the effects of
lonidamine (LND, 100 mg/kg, i.p.) are similar for a number of xenograft models of human
cancer including DB-1
melanoma and HCC1806 breast, BT-474 breast, LNCaP prostate and A2870 ovarian
carcinomas. Following treatment with LND, each of these
tumors exhibits a rapid decrease in intracellular pH, a small decrease in extracellular pH, a concomitant monotonic decrease in
nucleoside triphosphate and an increase in
inorganic phosphate over a 2-3 h period. We have previously demonstrated that selective intracellular
tumor acidification potentiates response of this
melanoma model to
melphalan (7.5 mg/kg, i.v.), producing an estimated 89% cell kill based on
tumor growth delay analysis. We now show that, in both DB-1
melanoma and HCC1806
breast carcinoma, LND potentiates response to
doxorubicin, producing 95% cell kill in DB-1
melanoma at 7.5 mg/kg, i.v.
doxorubicin and 98% cell kill at 10.0 mg/kg
doxorubicin, and producing a 95% cell kill in HCC1806
breast carcinoma at 12.0 mg/kg
doxorubicin. Potentiation of
doxorubicin may result from
cation trapping of the weakly basic
anthracycline. Recent experience with the clinical treatment of
melanoma and other forms of human
cancer suggests that these diseases will probably not be cured by a single therapeutic procedure other than surgery. A multimodality therapeutic approach will be required. As a potent modulator of
tumor response to N-mustards and
anthracyclines as well as
tumor thermo- and radiosensitivity, LND promises to play an important clinical role in the management and possible complete local control of a number of prevalent forms of human
cancer.