Etoposide with lonidamine or pentoxifylline as modulators of alkylating agent activity in vivo

In an effort to improve the additive anti-tumor efficacy of commonly used alkylating agents, the topoisomerase-II inhibitor etoposide was used in combination with either the mitochondrial poison and energy-depleting agent lonidamine or the hemorheologic agent and tumor-blood-flow-increasing agent pentoxifylline. In the FSaIIC murine fibrosarcoma system, these modulators were evaluated for modulation of whole-tumor cell killing vs. bone-marrow CFU-GM toxicity with the alkylating drugs CDDP, CTX, L-PAM or BCNU. Etoposide alone was essentially additive with the alkylating drugs for both tumor-cell and bone-marrow killing, except for BCNU, where a substantial increase in tumor-cell killing occurred (0.5 to 2.0 logs over the dose range of BCNU tested) without a significant increase in bone-marrow toxicity. Etoposide plus lonidamine was significantly more active than etoposide alone only with CTX and BCNU in tumor-cell vs. bone-marrow killing. Etoposide plus pentoxifylline was also most active with these two alkylating agents, where increases in tumor-cell killing of 0.5 to 1.0 log were observed. Hoechst-33342-defined tumor-cell sub-population studies revealed that etoposide significantly improved the killing of dim (putative hypoxic) cells by CDDP, but neither lonidamine nor pentoxifylline significantly improved killing of bright or dim cells together. With CTX, etoposide plus lonidamine or pentoxifylline substantially improved killing of dim cells over etoposide alone (each by about 0.8 logs). These data indicate that a therapeutic advantage may be achievable by combining etoposide with lonidamine or pentoxifylline for use with alkylating drugs.