Interactions of various nitroheterocyclic radiation sensitizers with cancer chemotherapeutic agents and radiation used in combination will be studied in an in vivo lung tumor model. Experiments are proposed to determine the effect on tumor cells growing in the lung of adding a sensitizer to a protocol combining the nitrosourea CCNU with localized radiation or the alkylating chemotherapeutic agent cyclophosphamide. Treatment efficacy will be assessed using endpoints of clonogenic cell survival, tumor regrowth delay and tumor-free animal survival. The influence that the inclusion of a sensitizer in such protocols has on secondary ovarian and renal metastases arising from lung tumors also will be established. Both the incidence of metastases to the ovaries and kidneys and their response to the treatment regimen will be measured. The nature of the interaction between such combined modality therapies will be determined through isoeffect plot (isobologram) analysis. It also is our objective to elucidate the role of pharmacokinetic changes (using HPLC analysis) in the combined modality protocols. The potential therapeutic benefit which may be achieved through the addition of a sensitizer to the different treatment regimen will be determined by measuring tumor responses as well as the early and late effects on critical normal tissues. Both tumor and normal tissue responses also will be studied under conditions where sensitizers are administered such that sensitizer pharmacokinetics achievable in human plasma are mimicked. Those treatment protocols giving rise to the largest therapeutic gains will be evaluated in xenografts of human lung cancer. These investigations should yield information which will improve our understanding of combined modality therapies and may guide the efforts for the most effective use of combinations of sensitizers, chemotherapeutic agents and radiation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA038637-03
Application #
3176750
Study Section
Radiation Study Section (RAD)
Project Start
1985-01-01
Project End
1987-12-31
Budget Start
1987-01-01
Budget End
1987-12-31
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Rochester
Department
Type
School of Medicine & Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Siemann, D W (1992) Cytotoxicity of dual function nitrofurans in rodent and human tumor cells. Int J Radiat Oncol Biol Phys 22:697-700
Richardson, M E; Siemann, D W (1992) Thiol manipulation as a means of overcoming drug resistance in a novel cyclophosphamide-induced resistant cell line. Int J Radiat Oncol Biol Phys 22:781-4
Lee, F Y; Flannery, D J; Siemann, D W (1991) Prediction of tumour sensitivity to 4-hydroperoxycyclophosphamide by a glutathione-targeted assay. Br J Cancer 63:217-22
Lee, F Y (1991) Glutathione diminishes the anti-tumour activity of 4-hydroperoxycyclophosphamide by stabilising its spontaneous breakdown to alkylating metabolites. Br J Cancer 63:45-50
Siemann, D W (1990) Enhancement of chemotherapy and nitroimidazole-induced chemopotentiation by the vasoactive agent hydralazine. Br J Cancer 62:348-53
Lee, F Y; Siemann, D W; Sutherland, R M (1989) Changes in cellular glutathione content during adriamycin treatment in human ovarian cancer--a possible indicator of chemosensitivity. Br J Cancer 60:291-8
Siemann, D W (1989) Do in vitro studies of potential lethal damage repair predict for in situ results? Int J Radiat Biol 56:567-71
Siemann, D W; Flaherty, A A; Penney, D P (1989) Effect of thiol manipulation on chemopotentiation by nitroimidazoles. Int J Radiat Oncol Biol Phys 16:1341-5
Siemann, D W (1989) The chemosensitizing and cytotoxic effects of RSU 1164 and RSU 1165 in a murine tumor model. Int J Radiat Oncol Biol Phys 16:1115-8
Siemann, D W; Alliet, K L; Macler, L M (1989) Manipulations in the oxygen transport capacity of blood as a means of sensitizing tumors to radiation therapy. Int J Radiat Oncol Biol Phys 16:1169-72

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