Motexafin gadolinium: a redox active drug that enhances the efficacy of bleomycin and doxorubicin.
The effect of motexafin gadolinium (MGd), a redox mediator, on tumor response to doxorubicin (Dox) and bleomycin (Bleo) was investigated in vitro and in vivo. MES-SA human uterine sarcoma cells were studied in vitro using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide viability assay. Rif-1, a murine fibrosarcoma cell line, was studied using a clonogenic survival assay. Tumor growth delay assays were performed using the EMT-6 murine mammary sarcoma cell line in BALB/c mice. MGd (25-100 microM) produced dose-dependent enhancement of Bleo cytotoxicity to MES-SA cells. The IC(50) for Bleo was reduced by approximately 10-fold using 100 microM MGd. In clonogenic assays using Rif-1 cells, MGd enhanced the activity of Bleo approximately 1000-fold. This effect was shown to be mediated, in part, by MGd inhibition of potentially lethal damage repair. MGd enhanced the tumor response to bleomycin and Dox in vivo. MGd had no significant effect on the systemic exposure to Dox (expressed in terms of the plasma area under the curve, 0-24 h) and did not increase Dox myelosuppression. MGd enhanced the effectiveness of the redox active drugs, Bleo and Dox.
Miller
R A
RA
Pharmacyclics, Inc., 995 East Arques Avenue, Sunnyvale, CA 94085, USA.
Woodburn
K W
KW
Fan
Q
Q
Lee
I
I
Miles
D
D
Duran
G
G
Sikic
B
B
Magda
D
D
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001761:Bleomycin / Q000494:pharmacology / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control; D017319:Photosensitizing Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D008665:Metalloporphyrins; D017319:Photosensitizing Agents; D001761:Bleomycin; C437683:motexafin gadolinium; D004317:Doxorubicin