Carbogen and Nicotinamide Increase Blood Flow and 5-Fluorouracil Delivery but not 5-Fluorouracil Retention in Colorectal Cancer Metastases in Patients

• Published in: Clinical cancer research 2006-05, Vol.12 (10), p.3115-3123
• Main Authors: GUPTA, Nishi, SALEEM, Azeem, PRICE, Patricia M, KÖTZ, Barbara, OSMAN, Safiye, ABOAGYE, Eric O, PHILLIPS, Robert, VERNON, Clare, WASAN, Harpreet, JONES, Terry, HOSKIN, Peter J
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Administration, Inhalation; Administration, Oral; Aged; Antimetabolites, Antineoplastic - pharmacokinetics; Antineoplastic agents; Biological and medical sciences; Blood Flow; Carbogen; Carbon Dioxide - pharmacology; Chemotherapy; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Delivery. Postpartum. Lactation; Drug Interactions; Female; Fluorouracil - pharmacokinetics; Gastroenterology. Liver. Pancreas. Abdomen; Gynecology. Andrology. Obstetrics; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - secondary; Male; Medical sciences; Middle Aged; Niacinamide - pharmacology; Nicotinamide; Oxygen - pharmacology; Pharmacology. Drug treatments; Positron Emission Tomography; Radiation-Sensitizing Agents - pharmacology; Regional Blood Flow; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tissue Distribution; Tumors; Vitamin B Complex - pharmacology
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-0513

Purpose: To examine whether carbogen and nicotinamide increases 5-fluorouracil (5-FU) delivery to colorectal cancer metastases. Experimental Design: Six patients were scanned using positron emission tomography. Two scans were done to coincide with the start of separate chemotherapy cycles. At the second positron emission tomography session, 60 mg/kg nicotinamide was given orally 2 to 3 hours before 10-minute carbogen inhalation. In the middle of carbogen treatment, [ 15 O]H 2 O (to measure regional tissue perfusion) and then [ 18 F]5-FU (to measure 5-FU tissue pharmacokinetics) were administered. Results: Regions of interest were drawn in 12 liver metastases, 6 spleens, 6 livers, and 12 kidneys. Nicotinamide and carbogen administration increased mean blood p O 2 from 93 mm Hg (95% confidence interval, 79-198) to 278 mm Hg (95% confidence interval, 241-316; P = 0.031). Regional perfusion (mL blood /min/mL tissue ) increased in metastases (mean change = 52%, range −32% to +261%, P = 0.024), but decreased in kidney (mean change = −42%, range −82% to −11%, P = 0.0005) and liver (mean change = −34%, range −43% to −26%, P = 0.031). 5-FU uptake at 3.75 minutes (m 2 /mL) increased in tumor (mean change = 40%, range −39% to +196%, P = 0.06) and decreased in kidney (mean change = −25%, range −71% to 12%, P = 0.043). 5-FU delivery measured as K 1 increased in tumor (mean change = 74%, range −23% to +293%, P = 0.0039). No differences were seen in [ 18 F]5-FU tumor exposure (net area under curve) and retention. Conclusion: Nicotinamide and carbogen administration can increase 5-FU delivery to colorectal cancer liver metastases. Despite an increase in perfusion and 5-FU delivery, the effects were not directly related and did not increase 5-FU retention or tissue exposure.