Improved tumor response by combining radiation and the vascular-damaging drug 5,6-dimethylxanthenone-4-acetic acid

The interaction between 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and ra diation was investigated in two different mouse tumor models and a normal m ouse tissue. C3H mouse mammary carcinomas transplanted in the feet of CDF1 mice and KHT mouse sarcomas growing in the leg muscles of C3H/HeJ mice were used. DMXAA was dissolved in saline and injected intraperitoneally. Tumors were irradiated locally in nonanesthetized mice, and response was assessed using tumor growth for the C3H mammary carcinoma and in vivo/in vitro clon ogenic cell survival for the KHT sarcoma. DMXAA alone had an antitumor effe ct in both tumor types, but only at doses above 15 mg/kg. DMXAA also enhanc ed radiation damage, and again there was a threshold dose. No enhancement w as seen in the C3H mammary carcinoma at 10 mg/kg and below, while in the KH T sarcoma, doses above 15 mg/kg were necessary. This enhancement of radiati on damage was also dependent on the sequence of and interval between the tr eatments with DMXAA and radiation. Combining radiation with DMXAA at the ma ximum tolerated dose (i.e., the highest dose that could be injected without causing any lethality) of either 20 mg/kg (CDF1 mice) or 17.5 mg/kg (C3H/H eJ mice) gave an additive response when the two agents were administered si multaneously. Even greater antitumor effects were achieved when DMXAA was a dministered 1-3 h after irradiation. However, when administration of DMXAA preceded irradiation, the effect was similar to that seen for radiation alo ne, suggesting that appropriate timing is essential to maximize the utility of this agent. When such conditions were met, DMXAA was found to increase the tumor response significantly in the absence of an enhancement of radiat ion damage in normal skin, thus giving rise to therapeutic gain. (C) 2001 b y Radiation Research Society.