In an effort to increase the efficacy of several
antineoplastic alkylating agents (CDDP,
L-PAM, CTX, or
BCNU), we examined the effect of the modulator
Fluosol-DA/
carbogen in combination with a second modulator, either
lonidamine or
pentoxifylline, on the survival of FSaIIC
tumor cells and of bone marrow CFU-GM from
tumor-bearing C3H mice.
Fluosol-DA/
carbogen increased the
tumor-cell killing activity of each
alkylating agent by about 10 times. In contrast,
lonidamine alone did not significantly increase the cytocidal activity of any of the
alkylating agents tested. However, in combination with
Fluosol-DA/
carbogen, the use of
lonidamine produced about a 100-fold increase in the
tumor cell kill achieved with CDDP as compared with CDDP alone. No increase in
tumor cell kill over that produced with the single modulator
Fluosol-DA/
carbogen was seen following the addition of
lonidamine to the combination treatment with
L-PAM, CTX, or
BCNU. Unfortunately, although neither
lonidamine nor
Fluosol-DA/
carbogen alone significantly increased
alkylator toxicity to bone marrow CFU-GM, the combination of modulators increased the toxicity of each
alkylating agent to bone marrow by about 10 times.
Pentoxifylline caused an increase in
alkylator activity against the FSaIIC
fibrosarcoma only when used with
BCNU; this effect was further augmented by the addition of
Fluosol-DA/
carbogen. The combination of modulators
pentoxifylline plus
Fluosol-DA/
carbogen was more effective than
Fluosol-DA/
carbogen alone only when the former was used with
BCNU, whereas only minimal increases in
tumor-cell killing activity were obtained with this modulator combination and CDDP,
L-PAM, or CTX.
Pentoxifylline increased the bone marrow CFU-GM toxicity of
L-PAM by about 10 times. The bone marrow CFU-GM toxicity was further increased by
Fluosol-DA/
carbogen, as was the toxicity of each of the other
alkylating agents.
Lonidamine plus
Fluosol-DA/
carbogen may be useful in increasing the therapeutic efficacy of CDDP, and the combination of
pentoxifylline plus
Fluosol-DA/
carbogen might improve the antitumor activity of
BCNU.