The hypoxic cytotoxin SR 4233 increases the effectiveness of radioimmunotherapy in mice with human non-Hodgkin's lymphoma xenografts.
OBJECTIVE
To determine if either the hypoxic cell radiosensitizer etanidazole (SR 2508) or the hypoxic cytotoxin SR 4233 could improve the effectiveness of radioimmunotherapy.


METHODS
LC4 (an IgG1 monoclonal antibody directed toward malignant T cells) and MB-1 (an irrelevant isotype-matched control antibody) were injected intraperitoneally into severe combined immunodeficient phenotype mice with human cutaneous T cell lymphoma xenografts in order to determine the distribution of the antibodies in the tumors and normal tissues as a function of time. Computerized-pO2-histography was used to measure the median oxygen tension in the tumors. Tumor-bearing mice were treated with: (a) LC4; (b) 90Y-LC4; (c) 90Y-MB-1; (d) whole body irradiation delivered via an external 137Cs source; (e) etanidazole and 90Y-LC4; (f) SR 4233 and 90Y-LC4; (g) etanidazole; and (h) SR 4233. An additional group of mice received no treatment and served as controls. A tumor growth delay assay was used to assess the effectiveness of the different treatment regimens.


RESULTS
LC4 accumulated in the tumors to a significantly greater extent than MB-1 (p < 0.001) and reached a peak concentration in the tumors 5 days post-injection. The human cutaneous T cell lymphoma xenografts had a relatively low median oxygen tension. LC4 by itself was able to produce a minor decrease in tumor size (control vs. LC4; p = 0.001). 90Y-LC4 produced greater tumor growth delay than LC4 alone (LC4 vs. 90Y-LC4; p = 0.01); however, the Yttrium-90 caused neutropenia and weight loss. The 90Y-labeled tumor-specific and non-specific antibodies both exerted greater tumor growth delay than externally delivered whole body irradiation (p < or = 0.03) due to preferential uptake of the antibodies in the tumors. Etanidazole and SR 4233 by themselves did not significantly inhibit the growth of the tumors. Etanidazole did not significantly enhance the tumor growth delay produced by 90Y-LC4 (90Y-LC4 vs etanidazole and 90Y-LC4, p = 0.13). SR 4233, on the other hand, did enhance the tumor growth delay produced by 90Y-LC4 (90Y-LC4 vs. SR 4233 and 90Y-LC4, p = 0.046). The neutropenia and weight loss caused by 90Y-LC4 were exacerbated slightly (< 10%) by the administration of SR 4233.


CONCLUSIONS
A first generation hypoxic cytotoxin, SR 4233, was able to enhance the tumor growth delay produced by radioimmunotherapy in severe combined immunodeficient phenotype mice with human cutaneous T cell lymphoma xenografts.
Wilder
R B
RB
Dept. of Radiation Oncology, Stanford University, CA 94305.
McGann
J K
JK
Sutherland
W R
WR
Waller
E K
EK
Minchinton
A I
AI
Goris
M L
ML
Knox
S J
SJ
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D017341:Etanidazole / Q000627:therapeutic use*; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000532:radiotherapy*; D051379:Mice; D016513:Mice, SCID; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D016499:Radioimmunotherapy; D000077704:Tirapazamine; D014183:Transplantation, Heterologous; D014227:Triazines / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D014227:Triazines; D000077704:Tirapazamine; D017341:Etanidazole