Dynamics of tumor oxygenation, CD31 staining and transforming growth factor-beta levels after treatment with radiation or cyclophosphamide in the rat 13762 mammary carcinoma.
OBJECTIVE
Tumors are dynamic tissues that undergo marked molecular, biochemical, and physiologic changes in response to cytotoxic anticancer therapies. Understanding the changes in tumor oxygenation and transforming growth factor-beta expression may allow improved treatment regimens to be developed.


METHODS
The effects of a single dose of radiation therapy (20 Gy) or a single dose of chemotherapy (cyclophosphamide, 250 mg/kg) on several molecular and physiologic parameters of the rat 13762 mammary carcinoma growing subcutaneously in female Fischer 344 rats were explored.


RESULTS
Treatment of the tumor-bearing animals with 20 Gy of radiation killed about two logs (99%) of the 13762 tumor cells, and treatment with cyclophosphamide (250 mg/kg) killed about 1.5 logs (95%) of the 13762 tumor cells. Hypoxia, as determined by a pO2 electrode, initially decreased in the tumors of treated animals until 6 h. posttreatment and then increased, so that 24 h. after administration of the radiation therapy or the chemotherapy the number of intratumoral vessels as determined by CD31 staining increased until about 24 h after cytotoxic therapy. Transforming growth factor-beta1, measured by radioimmunoassay, peaked in the serum between 6 h and 18 h and again between 72 h and 96 h after radiation therapy and peaked in the tumor at 24 h and again at 72 h after radiation therapy. The first serum peak after cyclophosphamide was 3 h after drug injection, with second peaks at 36 h and 48 h after drug administration. In the tumor, transforming growth factor-beta1 peaked between 6 h and 8 h after drug administration and again 36 h and 72 h after drug. Apoptosis was maximal 6 h after 20 Gy and 24 h after cyclophosphamide. Vascular endothelial growth factor was also increased in tumors after cytotoxic therapy.


CONCLUSIONS
These changes in the tumor physiologic status are sufficient to protect the tumor from a second cytotoxic insult administered days afterwards and to result in a restructuring of the tissue.
Kakeji
Y
Y
Dana-Farber Cancer Institute and Joint Center for Radiation Therapy, Boston, MA 02115, USA.
Maehara
Y
Y
Ikebe
M
M
Teicher
B A
BA
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000032:analysis; D015687:Cell Hypoxia / Q000187:drug effects / Q000528:radiation effects; D003520:Cyclophosphamide / Q000494:pharmacology*; D016228:Endothelial Growth Factors / Q000378:metabolism; D005260:Female; D008222:Lymphokines / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000532:radiotherapy; D010101:Oxygen Consumption / Q000187:drug effects* / Q000528:radiation effects*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D016212:Transforming Growth Factor beta / Q000097:blood / Q000187:drug effects* / Q000528:radiation effects*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; D016228:Endothelial Growth Factors; D008222:Lymphokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D003520:Cyclophosphamide