It is proposed to continue to investigate whether the application of circadian time-based chemotherapy can minimize drug toxicity and maximize its anticancer activity. This work will focus entirely upon the study of the circadian timing of infusional fluoropyrimidine chemotherapy. A multi-center clinical study utilizing single agent fluorodeoxyuridine will be performed in patients with metastatic progressive measurable renal cell carcinoma (RCC). This application expands the clinical study of chronopharinacodynamic questions from Albany Medical College to five additional centers with great independent interest in fluoropyrimidine chronopharmacology and/or kidney cancer. Dr. Robert Diasio at the University of Alabama in Birmingham, Dr. Robert Huben at Roswell Park Memorial Institute, Dr. Ace Allen at the University of Kansas, Dr. Georg Bjarnason at the Toronto-Bayview Hospital and Dr. Elwin Fraley at the University of Minnesota have each pledged to participate in the proposed study. Good performance status, previously untreated patients with measurable, progressive, metastatic RCC will be studied using a two-armed design which randomly assigns circadian infusion pattern. Based upon extensive preclinical murine and clinical phase I and phase II study of infusional FUDR in nearly 250 patients this agent will be delivered either by standard 14-day constant rate infusion or multi-step quasi-sinusoidal infusion peaking between 8 p.m. and 2 a.m. each day, repeated every 28 days. Because of well documented inter-individual differences in fluoropyrimidine tolerance and because of the likely importance of fluoropyrimidine dose intensity each study will employ individual FUDR dose escalation, allowing each evaluable patient to receive her or his highest safely tolerated fluoropyrimidine dose intensity. This clinical study will test the effect of circadian infusion shape upon: drug toxicity; maximum tolerated dose; mean dose intensity; frequency, quality and duration of tumor response; and patient survival.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA031635-10
Application #
2088168
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1982-03-01
Project End
1996-07-31
Budget Start
1994-08-11
Budget End
1995-07-31
Support Year
10
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Albany Medical College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Albany
State
NY
Country
United States
Zip Code
12208
Grutsch, James F; Ferrans, Carol; Wood, Patricia A et al. (2011) The association of quality of life with potentially remediable disruptions of circadian sleep/activity rhythms in patients with advanced lung cancer. BMC Cancer 11:193
Hrushesky, William J M; Sothern, Robert B; Du-Quiton, Jovelyn et al. (2011) Sunspot dynamics are reflected in human physiology and pathophysiology. Astrobiology 11:93-103
Retsky, Michael W; Hrushesky, William J M; Gukas, Isaac D (2009) Hypothesis: primary antiangiogenic method proposed to treat early stage breast cancer. BMC Cancer 9:7
Oh, Eun-Young; Wood, Patricia A; Yang, Xiaoming et al. (2009) Discovery of candidate genes and pathways that may help explain fertility cycle stage dependent post-resection breast cancer outcome. Breast Cancer Res Treat 118:345-59
Wood, Patricia A; Du-Quiton, Jovelyn; You, Shaojin et al. (2006) Circadian clock coordinates cancer cell cycle progression, thymidylate synthase, and 5-fluorouracil therapeutic index. Mol Cancer Ther 5:2023-33
Wood, Patricia A; Bove, Kathleen; You, Shaojin et al. (2005) Cancer growth and spread are saltatory and phase-locked to the reproductive cycle through mediators of angiogenesis. Mol Cancer Ther 4:1065-75
Bove, Kathleen; Lincoln, David W; Wood, Patricia A et al. (2002) Fertility cycle influence on surgical breast cancer cure. Breast Cancer Res Treat 75:65-72
Kobayashi, Minoru; Wood, Patricia A; Hrushesky, William J M (2002) Circadian chemotherapy for gynecological and genitourinary cancers. Chronobiol Int 19:237-51
Bjarnason, G A; Jordan, R C; Wood, P A et al. (2001) Circadian expression of clock genes in human oral mucosa and skin: association with specific cell-cycle phases. Am J Pathol 158:1793-801
Lincoln 2nd, D W; Hrushesky, W J; Wood, P A (2000) Circadian organization of thymidylate synthase activity in normal tissues: a possible basis for 5-fluorouracil chronotherapeutic advantage. Int J Cancer 88:479-85

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