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Table 1 Effect of Bcl-2 and GSH depletion on the in vivo response of A375 melanoma to chemoradiotherapy.

From: Glutathione and Bcl-2 targeting facilitates elimination by chemoradiotherapy of human A375 melanoma xenografts overexpressing bcl-xl, bcl-2, and mcl-1

 

Tumor volume measurement (mm3)

Days after treatment

 

1

  

15

 

Treatment

PS

G3139

G3139+ACV+VRP

PS

G3139

G3139+ACV+VRP

None

192 ± 59

138 ± 28

175 ± 61

807 ± 240

953 ± 330

618 ± 265

PAC.PBP

153 ± 61

97 ± 31

74 ± 30*+

> 1000

731 ± 148

547 ± 138

DNR

220 ± 70

156 ± 49

117 ± 44*

> 1000

> 1000

> 1000

PAC.PBP + DNR

83 ± 26++

66 ± 18++

45 ± 12**++

> 1000

488 ± 177

352 ± 95

X rays

263 ± 88

84 ± 26**+

71 ± 25**++

> 1000

769 ± 260

641 ± 189

X rays + PAC.PBP

150 ± 44

93 ± 15*+

105 ± 38

643 ± 167

161 ± 75**++

96 ± 36**++

X rays + DNR

246 ± 71

96 ± 36**

53 ± 9**++

926 ± 225

694 ± 166

502 ± 190**

X rays + PAC.PBP + DNR

42 ± 14++

< 20

< 20

514 ± 116+

43 ± 12**++

N.D.

  1. The treatment regimen is indicated in the scheme placed above the table. Mice were fed ad libitum on a GED (see Methods) starting 1 week before tumor inoculation. Verapamil (VRP, 1 mg/kg) and acivicin (ACV, 2 mg/kg) were given i.p. daily (1 dose × day) starting 7 days after tumor cell inoculation (days 7 to 16). G3139 (20 mg/kg) was given i.v. on days 7, 10, 13, and 16. Paclitaxel protein-binding particles [PAC.PBP, 32.5 mg/kg (human MTD × 5)] was given i.v. on days 7 and 10. Daunorubicin [DNR, 3.125 mg/kg (human MTD × 2.5)] was given i.v. on days 13 and 16. Animal doses of chemotherapy were calculated using NCI guidelines (www.cancer.gov) and the conversion factor for mice published by the FDA (www.fda.gov). Mice received fractionated X-ray therapy (15 Gy/day focused on the tumor) on days 8 and 9. Total X-ray dose was selected, as effective and safe, after testing a range of 5 to 40 Gy in the absence or in the presence of the full combined therapy (not shown). Mice were sacrificed when tumor volume was > 1000 mm3. Tumor size on day 7 after inoculation was, in all cases, of 50-75 mm3. Body weight of mice treated with the full combination was approximately 75% and 83% of controls (treated with physiological saline) 1 or 15 days, respectively, after the treatment. Data are means ± S.D. for 18 to 20 different mice. N.D., nondetectable. Histologic examination (see Methods) confirmed that, in 16 of 20 (80%) mice, the full treatment achieved a complete tumor regression. *P < 0.05, **P < 0.01 comparing for each condition G3139- or G3139 + VRP + ACV-treated tumor-bearing mice versus treatment with physiologic saline. +P < 0.05, ++P < 0.01 comparing, in mice treated with physiologic saline, G3139, or G3139 + VRP + ACV, all experimental conditions versus none under treatment.
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Journal of Translational Medicine

ISSN: 1479-5876

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