Improved Tumor Response by Combining Radiation and the Vascular-Damaging Drug 5,6-Dimethylxanthenone-4-acetic Acid

Abstract

The interaction between 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and radiation was investigated in two different mouse tumor models and a normal mouse 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 clonogenic cell survival for the KHT sarcoma. DMXAA alone had an antitumor effect in both tumor types, but only at doses above 15 mg/kg. DMXAA also enhanced radiation damage, and again there was a threshold dose. No enhancement was seen in the C3H mammary carcinoma at 10 mg/kg and below, while in the KHT sarcoma, doses above 15 mg/kg were necessary. This enhancement of radiation damage was also dependent on the sequence of and interval between the treatments with DMXAA and radiation. Combining radiation with DMXAA at the maximum 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/HeJ mice) gave an additive response when the two agents were administered simultaneously. Even greater antitumor effects were achieved when DMXAA was administered 1-3 h after irradiation. However, when administration of DMXAA preceded irradiation, the effect was similar to that seen for radiation alone, 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 radiation damage in normal skin, thus giving rise to therapeutic gain.

Vascular targeting agents enhance chemotherapeutic agent activities in solid tumor therapy

“…As previously described by us 11,18,22 and others, 5,6,10,12,20,21 by 24 hr after drug exposure, viable tumor cells were detectable only at the periphery of the tumors adjacent to the surrounding normal tissues (data not shown). These histologic changes were probably the consequence of the rapid and widespread shutdown in vascular function seen in tumors after CA4DP or DMXAA exposure (Fig.…”

“…These results are consistent with those of other groups who also have noted the failure of DMXAA to be effective on its own except at doses approaching the MTD. 6,8,20,22 In contrast, the tubulin binding agent CA4DP achieved its vascular (Fig. 2) and secondary tumor cell death effects (Fig.…”

“…[13][14][15] This approach has proved effective in a number of preclinical investigations combining DMXAA or CA4DP with conventional anticancer treatments such as chemotherapy 13,14,24,26 -28 or radiotherapy. 11,17,21,22,26 Although results to date have largely been encouraging, a number of critical questions concerning the use of vascular targeting agents in such settings remain. For example, it is not clear whether 1 vascular targeting agent has a therapeutic advantage over another or whether combination therapy will allow the use of lower doses of the vascular targeting agent while maintaining antitumor efficacy.…”

“…Thus, to realize the potential of these agents fully, it would appear necessary to combine them with conventional anticancer therapies. 14,15,20 Several combination therapies involving DMXAA (including bioreductive agents, 3,20 external beam irradiation, 21,22 radioimmunotherapy, 23 chemotherapy 24 or enzyme-activated prodrug therapy 25 ) have been examined. Similarly, CA4DP has been combined with other agents (particularly radiotherapy 11,17,26 and chemotherapy 14,26 -28 ) in a variety of tumor models.…”

Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer

“…In animal models, this culminates in extensive tumour necrosis predominantly within the tumour core (Zwi et al, 1994;Laws et al, 1995;Ching et al, 1999Ching et al, , 2004Joseph et al, 1999). The therapeutic potential of ASA404 appears to lie in its combination with other treatments (Wilson et al, 1998;Murata et al, 2001). In animal models, ASA404 acted synergistically with chemotherapy (Pruijn et al, 1997;Siim et al, 2003;McKeage and Kelland, 2006); therapeutic gains were most striking with taxanes.…”