Effect of 3-fluorothalidomide and 3-methylthalidomide enantiomers on tumor necrosis factor production and antitumor responses to the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA).
5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is an antivascular drug that induces tumor necrosis factor (TNF) in mice. Thalidomide inhibits TNF induction by DMXAA and also potentiates its antitumor activity. We investigated whether these effects were enantiomer specific, using the R- or S-enantiomers of two nonracemizable thalidomide analogues. Racemic 3-fluorothalidomide (3FThal) and racemic 3-methylthalidomide (3MeThal) were separated into enantiomers of greater than 98% optical purity using preparative chiral column chromatography. C57Bl/6 mice implanted with subcutaneous Colon 38 tumors were treated with DMXAA (25 mg/kg) alone or together with the pure R- or S-enantiomers by a single i.p. injection. TNF levels in the serum or tumor tissues 3 h after treatment were measured using ELISAs and tumor growth was also measured. 3FThal and 3MeThal, at their respective single maximum tolerated doses (MTD) of 15 and 50 mg/kg, were more toxic in mice than thalidomide (100 mg/kg). The R- and S-enantiomers of either 3FThal or 3MeThal, at their respective MTD, inhibited DMXAA-induced TNF activity in serum and tumor tissue, but no significant differences were observed between the enantiomers. Coadministration of racemic or enantiomers of 3FThal or 3MeThal at their respective MTD did not potentiate the antitumor responses above that obtained with DMXAA alone, and no enantioselectivity was apparent. We conclude that there is no advantage in using the nonracemizable thalidomide analogues to improve the antitumor activity of DMXAA.
Chung
Francisco
F
Auckland Cancer Society Research Center, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
Palmer
Brian D
BD
Muller
George W
GW
Man
Hon-Wah
HW
Kestell
Phillip
P
Baguley
Bruce C
BC
Ching
Lai-Ming
LM
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007274:Injections, Intraperitoneal; D020714:Maximum Tolerated Dose; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000627:therapeutic use*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D044004:Xanthones / Q000008:administration & dosage / Q000627:therapeutic use*
C114058:3'-methylthalidomide; C487383:3-fluorothalidomide; D020533:Angiogenesis Inhibitors; D014409:Tumor Necrosis Factor-alpha; D044004:Xanthones; C066668:vadimezan; D013792:Thalidomide