title: Combined-modality radioimmunotherapy: synergistic effect of paclitaxel and additive effect of bevacizumab.
abstract: BACKGROUND
  This study was undertaken to investigate the effect of paclitaxel and bevacizumab on the therapeutic efficacy of (90)Y-labeled B3 monoclonal antibody, directed against Le(y) antigen, for the treatment of Le(y)-positive A431 tumors implanted subcutaneously in the right hind flank of nude mice.
  
  
  METHODS
  When the tumor size reached ~200 mm(3), the mice received a single dose of intravenous (iv) (90)Y-labeled B3 (60 μCi/150 μg or 100 μCi/150 μg B3), intraperitoneal paclitaxel (40 mg/kg) or iv bevacizumab (5 mg/kg) for monotherapy. To investigate the effect of combined therapies on survival, the mice were treated with two or three agents in the following combinations: (90)Y-B3 on day 0 and paclitaxel on day 1; bevacizumab on -1 day and (90)Y-B3 on day 0; bevacizumab on -1 day and paclitaxel on day 1; bevacizumab, (90)Y-B3 and paclitaxel each at 1-day intervals. The mice with no treatment were used as a control. The tumor volume at 1000 mm(3) was used as a surrogate end point of survival.
  
  
  RESULTS
  Compared to control animals, paclitaxel delayed tumor growth with a significantly longer median survival time (P<.001), whereas bevacizumab alone showed a less pronounced effect on a median survival time (P=.18). (90)Y-B3 increased the median survival time in a dose-dependent manner (P<.05). The combined therapy of bevacizumab with paclitaxel produced a trend toward an increase of the median survival time compared to paclitaxel alone (P=.06), whereas bevacizumab combined with (90)Y-B3 showed a statistically insignificant increase in the median survival time compared to (90)Y-B3 alone (P=.25). The tumor sizes of all animals in these groups reached the surrogate end point of survival by day 35. In contrast, the combined therapy involving (90)Y-B3 with paclitaxel showed a striking synergistic effect in shrinking tumors and prolonging the survival time (P<.001); on day 120, three of nine mice (33%) and six of six mice (100%) were alive without tumor when treated with 60 μCi (90)Y-B3 and 100 μCi (90)Y-B3, respectively. The addition of bevacizumab treatment 1 day before the combined therapy of 60 μCi (90)Y-B3 with paclitaxel did not produce a statistically significant increase in survival when compared to the (90)Y-B3 with paclitaxel (P>.10). Fluorescence microscopy analysis indicated that paclitaxel increased, whereas bevacizumab decreased, the accumulation and penetration of Alexa Fluor 647-B3 into tumor microenvironment compared to the control (P<.05).
  
  
  CONCLUSIONS
  Our findings on the paclitaxel effect support a hypothesis that the increased tumor accumulation and penetration of (90)Y-B3 as well as the high radiosensitization of tumor cells by paclitaxel may be the major factors responsible for the synergistic effect of the combined therapy involving (90)Y-B3 with paclitaxel.
authors.affiliation: Radiopharmaceutical Laboratory, Nuclear Medicine, Clinical Center, National Cancer Institute/NIH, Bethesda, MD 20892, USA.
authors.forename: Beom-Su
authors.initials: BS
authors.lastname: Jang
authors.forename: Sang-Myung
authors.initials: SM
authors.lastname: Lee
authors.forename: Hyung Sub
authors.initials: HS
authors.lastname: Kim
authors.forename: In Soo
authors.initials: IS
authors.lastname: Shin
authors.forename: Faezeh
authors.initials: F
authors.lastname: Razjouyan
authors.forename: Shutao
authors.initials: S
authors.lastname: Wang
authors.forename: Zhengsheng
authors.initials: Z
authors.lastname: Yao
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Dreher
authors.forename: Chang H
authors.initials: CH
authors.lastname: Paik
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D000068258:Bevacizumab; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D016499:Radioimmunotherapy / Q000379:methods*; D023041:Xenograft Model Antitumor Assays; D015021:Yttrium Radioisotopes / Q000627:therapeutic use
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015021:Yttrium Radioisotopes; D000068258:Bevacizumab; D017239:Paclitaxel