Either sS by co-administration of DMXAA and 5-HT, either singly or together. A BAT for SN 23816, DMXAA provided a significant increase ASA404 DMXAA in anti-tumor activity of t, With an average growth rate of 11 days delay Delay for this combination, and it rose again to 26.5 days by the uptake of 5-HT . The effect of 5-HT, when combined with SN 23,816, plus DMXAA was statistically significant in both experiments, w While 5-HT itself no Erh Increase in activity T of SN 23816th The effect of different doses of 5-HT in the combined treatment was studied in separate experiments. Toxicity t H Te, as was the Ver Change in the K Rpergewichts assessed increased by 5-HT Ht. The effect of 5-HT on the anti-tumor response was statistically significant in both tests, only the h Next dose of 5-HT.
Antitumor activity Was reduced t if the bioreductive Drug Administration galv Siege was this decrease was statistically significant at 24 h, but not 2 h DISCUSSION For each endpoint of this study was the dose-response relationship for the activity T of DMXAA against MCA MDAH nonlinear four tumors, with a threshold at about the H half of the maximum tolerated dose. This property DMXAA activity T been observed in many other studies. The demand for cans so close to the limit of toxicity t suggests that it will be difficult, the activity of t Show of DMXAA in humans if the therapeutic ratio Ratio’s similar to that of the mouse. Combination with exogenously administered 5-HT is of particular interest in that the antitumor activity of T Is enhanced by DMXAA significantly with little or no Erh Increase the toxicity t Home.
Erh Hte Antitumoraktivit t Of DMXAA concomitant administration of 5-HT was observed with the three tumors that were previously investigated, n Namely the breast MCA MDAH 4 in this study, tumors of the heart lon 38 and LS 174T human adenocarcinoma xenografts c lon. DMXAA/5HT Hnlichen agent combretastatin A-4 tubulin binding in its F Ability, inhibit tumor blood flow at doses well below the maximum tolerable Adjusted dose, although no direct comparison between these antivaskul Re therapy was performed. The potential of 5-HT, m May receive in connection with 5-HT3 receptor antagonists for the therapeutic ratio Improve ratio of DMXAA in human and warrants investigation.
It w Re also interesting to combine with DMXAA flow inhibitor KB R8498 new tumor with blood, which appears as an act 5-HT2 receptor agonist. The mechanism by the exogenous 5-HT improved tumor blood flow inhibition when it is not combined with DMXAA known. It may be that the two agents have independently-Dependent effects on tumor cells microvasculature. However, the observation that 5-HT, receptor antagonists inhibited cyproheptidine necrosis of the heart 38 by lon DMXAA or recombinant human TNF, and as t is the activity ox of TNF against Meth A fibrosarcoma of the sensitive 5-HT is inhibited by 5-HT receptor antagonist, led to the proposal, more, tt that downstream 5-HT can rts of TNF in mediating the effects ux DMXAA act. If this is the case, given a 5-HT Erh Increase the endogenous pathway. This is made unlikely Recent studies show that systemic concentrations of 5-HT is only slightly h Ago after DMXAA treatment, and that this increase is even after the treatment with antivaskul Re agent such as vinblastine, acting not observed on TNF. T .