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

Abstract

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, [ 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 À32% to +261%, P = 0.024), but decreased in kidney (mean change = À42%, range À82% to À11%, P = 0.0005) and liver (mean change = À34%, range À43% to À26%, P = 0.031). 5-FU uptake at 3.75 minutes (m 2 /mL) increased in tumor (mean change = 40%, range À39% to +196%, P = 0.06) and decreased in kidney (mean change = À25%, range À71% to 12%, P = 0.043). 5-FU delivery measured as K 1 increased in tumor (mean change = 74%, range À23% to +293%, P = 0.0039). No differences were seen in [ Although 5-fluorouracil (5-FU) dominates the chemotherapy of colorectal cancer, the response rate of advanced disease to the drug given as a single agent is only around 15% (1, 2). This poor response rate has stimulated research into approaches for increasing its therapeutic index, such as biochemical modulation (e.g., using folinic acid; ref. 1) and schedule alteration (e.g., continuous infusions rather than bolus administration, oral administration; ref. 2). The rationale behind changing the mode of 5-FU administration relates to its short biological half-life (10-20 minutes) and its S-phase-dependent activity, which limit the systemic exposure of drug and tumor cell kill (3, 4). Increasing the plasma levels of 5-FU can improve response and survival in patients (5, 6). However, additional improvements in 5-FU efficacy by increasing plasma drug levels are further limited by dose-limiting normal tissue toxicity, and other approaches for enhancing the efficacy of 5-FU are required.It is postulated that the administration of nicotinamide and carbogen to patients with metastatic colorectal cancer should selectively increase the uptake of 5-FU into a tumor, by increasing tumor blood flow, without changing the systemic exposure to the drug. The nicotinamide and carbogen combination is being explored as an approach for reducing tumor hypoxia, an important cause of cancer treatment resistance (7), and improving radiotherapy response (8 -11). Nicotinamide, an amide of vitamin B 3 , can increase tumor blood flow via a mechanism thought to involve the stabilization of the tumor microvasculature (reducing contractility and fluctuations in blood flow; refs. 12, 13) and a decrease in Cancer Therapy: Clinical

The Pharmacokinetic/Pharmacodynamic Pipeline: Translating Anticancer Drug Pharmacology to the Clinic

“…With regard to the independent physiological parameters associated with tumors, tumor blood flow is recognized to play a significant role in tumor drug uptake and exposure (26,27). Determination of blood flow rate in vivo usually involves the use of a diffusible indicator that is removed from tissue in proportion to blood flow based on the Kety-Schmidt principle (28) followed by measurements with external detectors, such as quantitative autoradiography, positron emission tomography, and magnetic resonance imaging.…”

Barrier protective use of skin care to prevent chemotherapy-induced cutaneous symptoms and to maintain quality of life in patients with breast cancer

“…42,43 In addition, there are indications that niacinamide supports the release of cytostatics from cells, depending on concentration, and therefore reduces their antiproliferative effects. 44 These effects of the topically applied and, therefore, only cutaneously bioavailable active substance are the basis for the hypothesis of a conditioning proactive use during cytostatic therapy. The above-mentioned additional effects concerning ceramide synthesis and anti-inflammation are cumulative.…”

Multiplexed imaging for diagnosis and therapy

“…Staggered injection of multiple short-lived radioisotopes including 15 O (t1/2 2.04 min), followed by 11 C (t1/2 20.33 min), and finally 18 F (t1/2 109.8 min) within a single visit enables co-dependent analysis to improve physiology and/or pharmacokinetic-pharmacodynamic assessment with minimal physiological perturbation. As applied to 5-fluorouracil in colorectal cancer [177][178][179] (Fig. 2b) and temozolomide in glioma 174,180 (Fig.…”

“…Hyperpolarised MR provides the advantage of tracking metabolism over several enzymatic steps, and PET provides sensitivity. For example, MR spectroscopic imaging with the hyperpolarised metabolite 13 C-pyruvate and FDG-PET were performed simultaneously in dogs with prostate cancer 179,181,182 . High tumour glycolysis was detectable via the increased relative conversion of 13 C-pyruvate to 13 C-lactate, ( -) resonance peaks were also increased) and FDG uptake.…”

“…Figures (ii-iv) adapted from ref. 179 with permission from AACR. c i-iv, Physiologic use of multiplexing PET demonstrated in the determination of the mechanism of action of temozolomide in glioma patients with 11 C-HCO3 -followed by 11 C-temozolomide in the same visit.…”