Marked potentiation of the antitumour activity of chemotherapeutic drugs by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA).

Abstract

To determine whether there is a therapeutic interaction between the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and nine chemotherapy drugs against an early-passage mouse mammary tumour (MDAH-MCa-4), and to investigate the mechanism of any such interaction. Female C3H/HeN mice bearing intramuscular MDAH-MCa-4 tumours were injected intraperitoneally with DMXAA (80 micro mol/kg) or chemotherapy drug (at a range up to the maximum tolerated dose) alone, or coadministered. A small reduction in the dose of the chemotherapy drug was required in most cases, but the increase in antitumour effect was much greater than the increase in host toxicity (body weight loss). The therapeutic gain increased in the order 5-fluorouracil (no gain)<(etoposide, carboplatin, cyclophosphamide, doxorubicin, cisplatin)<(docetaxel, vincristine)<paclitaxel. The interaction with paclitaxel (31.6 micro mol/kg) was striking, with coadministration of DMXAA extending the median tumour growth delay from 0.3 to 80 days with three of seven animals cured. The interaction showed a broad timing of the optimum with similar activity when paclitaxel was administered 4 h before to 1 h after DMXAA: No therapeutic synergy was obtained when paclitaxel was combined with the antivascular agent combretastatin A4 phosphate (227 micro mol/kg), which induced only transient blood flow inhibition in this tumour, measured using the H33342 perfusion marker. Paclitaxel did not enhance the antivascular activity of DMXAA: Plasma and tumour concentrations of paclitaxel (and carboplatin), measured by LC-MS and ICP-MS respectively, were not elevated by combination with DMXAA: There was a dramatic therapeutic interaction between DMXAA and standard chemotherapy drugs, particularly paclitaxel, against the MDAH-MCa-4 tumour, which was not due to a pharmacokinetic interaction or potentiation of antivascular activity. It is suggested that the major mechanism of synergy is killing of cells by DMXAA in poorly perfused regions of tumours that are inaccessible to chemotherapy drugs.