Effect of estrogenic perturbations on delta-aminolevulinic acid-induced porphobilinogen deaminase and protoporphyrin IX levels in rat Harderian glands, liver, and R3230AC tumors.
The Harderian gland in rodents highly expresses enzymes of the heme biosynthetic pathway that are responsible for porphyrin production. Interestingly, many of the steps in Harderian gland heme biosynthesis, including protoporphyrin production, are controlled hormonally. We hypothesized that estrogenic alterations, ovariectomy or tamoxifen administration, might also alter the response of porphobilinogen deaminase activity and/or protoporphyrin IX production to delta-aminolevulinic acid administration in the hormonally responsive R3230AC rat mammary adenocarcinoma. We also determined whether the response of the R3230AC tumor, borne on ovariectomized hosts, to delta-aminolevulinic acid-based photodynamic therapy was altered compared with tumors treated on intact hosts. Ovariectomy of female Fischer rats bearing the hormonally responsive R3230AC mammary adenocarcinoma caused a significant reduction in delta-aminolevulinic acid-induced protoporphyrin IX levels and porphobilinogen deaminase activity in tumors compared with levels in tumors from intact animals treated with delta-aminolevulinic acid. In contrast, although porphobilinogen deaminase activity in the Harderian gland from ovariectomized animals was reduced significantly compared with that in glands from intact animals, protoporphyrin IX levels were unaltered. Administration of the anti-estrogen tamoxifen to tumor-bearing rats resulted in a significant increase in porphobilinogen deaminase in both tumor and Harderian gland. Although administration of delta-aminolevulinic acid increased protoporphyrin IX levels in Harderian glands in tamoxifen-treated animals, tumor levels of protoporphyrin IX remained unaltered in the tamoxifen-treated rats. Treatment of R3230AC tumors with delta-aminolevulinic acid-based photodynamic therapy in ovariectomized rats resulted in a significantly reduced response compared with the same treatment regimen in intact animals, 4.9+/-0.39 versus 10.6+/-0.6 days to reach twice the initial tumor volume, respectively. These results indicate that the hormonal status of the host should be considered when treating hormonally sensitive tumors with delta-aminolevulinic acid-based photodynamic therapy.
Gibson
S L
SL
Department of Biochemistry and Biophysics and the UR Cancer Center, University of Rochester School of Medicine, and Dentistry, University of Rochester, NY 14642, USA.
Anderson
L T
LT
Havens
J J
JJ
Hilf
R
R
D000622:Aminolevulinic Acid / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006243:Harderian Gland / Q000201:enzymology*; D011163:Hydroxymethylbilane Synthase / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D010052:Ovariectomy; D010778:Photochemotherapy; D011524:Protoporphyrins / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013629:Tamoxifen / Q000494:pharmacology
D004965:Estrogen Antagonists; D004967:Estrogens; D011524:Protoporphyrins; D013629:Tamoxifen; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX; D011163:Hydroxymethylbilane Synthase