Allosteric effectors of hemoglobin as modulators of chemotherapy and radiation therapy in vitro and in vivo.
BACKGROUND
A series of molecules designed to be allosteric effectors of hemoglobin were examined for their potential as radiation sensitizers in vitro and in vivo and for their potential as chemosensitizers in vivo as well as for their antimetastatic effect.


RESULTS
At a concentration of 100 microM for 1 h prior to, during and for 1.5 h after radiation exposure, the allosteric effectors decreased the shoulder of the radiation survival curve of normally oxygenated EMT-6 cells and increased the slope of the radiation survival curves of hypoxic EMT-6 cells resulting in dose-modifying factors of 1.8 to 2.1. In vivo the allosteric effectors had antitumor activity against the Lewis lung carcinoma and produced primarily additive tumor growth delay when administered along with fractionated radiation therapy. When administered on days 4 through 18 after tumor implantation, the allosteric effectors, especially JP-7, RSR-13 and RSR-4, were highly effective antimetastatic agents in animals bearing Lewis lung carcinoma. In cell culture, simultaneous exposure to the allosteric effectors (at 100 microM) effectively sensitized EMT-6 cells to the effects of 4-hydroperoxycyclophosphamide, thiotepa and carboplatin. The allosteric effectors were not very cytotoxic toward EMT-6 tumor cells from tumors treated in vivo with single doses of each molecule nor were these agents very cytotoxic toward bone marrow CFU-GM taken from the same animals.


CONCLUSIONS
It is likely that the allosteric effectors have a molecular target in addition to hemoglobin. Other possible targets include hydroxymethyl-glutaryl-CoA reductase or microsomal cytochrome b5.
Teicher
B A
BA
Dana-Farber Cancer Institute and Joint Center for Radiation Therapy, Boston, MA 02115, USA. teicher_beverly_a@lilly.com
Wong
J S
JS
Takeuchi
H
H
Gravelin
L M
LM
Ara
G
G
Buxton
D
D
D000494:Allosteric Regulation; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000986:Antisickling Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000532:radiotherapy*; D003114:Colony-Forming Units Assay; D003131:Combined Modality Therapy; D005260:Female; D006454:Hemoglobins / Q000378:metabolism; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000532:radiotherapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D011422:Propionates / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000814:Aniline Compounds; D000986:Antisickling Agents; D006454:Hemoglobins; D011422:Propionates; D011838:Radiation-Sensitizing Agents; C067396:efaproxiral