Possible Interaction: Thalidomide and Vadimezan

“Abstract Background: Previous studies have demonstrated that coadministration of L-thalidomide with the novel antitumour agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) results in an increased area under the plasma concentration-time curve (AUC) of DMXAA, suggesting an explanation for the observed increase in the antitumour activity.”

“Coadministration of L-thalidomide in male mice resulted in a 23% increase in DMXAA AUC and a twofold increase in T1/2 (P<0.05).”

“Coadministration of thalidomide also significantly reduced the plasma clearance of DMXAA and cyclophosphamide.”

“In addition, the antitumour effects of the conventional cytotoxic drug cyclophosphamide and the tumour necrosis factor inducer 5,6-dimethylxanthenone-4-acetic acid (DMXAA) were found to be potentiated by thalidomide in mice bearing colon 38 adenocarcinoma tumours.”

“Co-administration of thalidomide increases the effective dose of DMXAA by reducing clearance but also, by inhibiting production of circulating TNF, reduces the host toxicity of DMXAA.”

“Co-administration of thalidomide potentiated the effects of DMXAA on both body temperature and haematocrit but surprisingly did not increase toxicity.”

“ Thalidomide is an anti-inflammatory agent that potentiates the anti-tumour activity of DMXAA but decreases induction of TNF in plasma.”

“ Thalidomide inhibits TNF induction by DMXAA and also potentiates its antitumor activity.”

“ConclusionsBoth cyclophosphamide and DMXAA have a pharmacokinetic interaction with thalidomide , increasing t1/2 and AUC.”

“Our previous work has shown that thalidomide potentiates the antitumour activity of both cyclophosphamide and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) against murine Colon 38 tumours.”

“Purpose: Coadministration of thalidomide , cyproheptadine or diclofenac has been shown to increase the area under the plasma concentration-time curve (AUC) of the novel antitumour agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in mice.”

“Coadministration of thalidomide increased the area under the concentration-time curve (AUC) of DMXAA by 1.8-fold in plasma, liver and spleen, and by 3.0-fold in tumour.”

“Coadministration of thalidomide , a modulator of cytokine production, potentiates the antitumour activity of DMXAA against the murine Colon 38 carcinoma in mice.”

“ Thalidomide , probably as the l-form, decreases the rate of elimination of DMXAA from plasma, spleen, liver and tumour by altering the rate of glucuronidation.”

“The reduction in the elimination of DMXAA by thalidomide may lead to a selective increase in exposure of tumour tissue to drug, providing a basis for its potentiation of antitumour activity.”

“ l-Thalidomide had a greater effect on DMXAA elimination (P < 0.01) than did d-thalidomide or the racemate.”

“Co-administration of thalidomide may represent a novel approach to improving selective intra-tumoural TNF-α production and anti-tumour efficacy of DMXAA.”

“Co-administration of thalidomide with DMXAA increased anti-tumour activity and increased intra-tumoural TNF-α production approximately tenfold over that obtained with DMXAA alone.”

“The increase in the anti-tumour action by thalidomide in combination with DMXAA corresponded to an increase in intra-tumoural TNF-α production.”

“While thalidomide improved the anti-tumour response to DMXAA , it had no effect on the anti-tumour action of LPS that did not induce a significant growth delay or cures against the Colon 38 tumour.”

“Our previous studies have shown that thalidomide , a potent inhibitor of TNF biosynthesis that has numerous biological effects, including inhibition of tumour angiogenesis, unexpectedly augments the anti-tumour response in mice to DMXAA.”

“We show here that thalidomide (100 mg kg(-1)) has no effect when administered with inactive doses of DMXAA, and that it must be given simultaneously with an active dose of DMXAA to have its maximum potentiating effect on the growth of the murine Colon 38 adenocarcinoma.”

“Unexpectedly, the drug thalidomide , while reducing the serum TNF response to DMXAA , potentiates its antitumour effect.”