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British Journal of Cancer (2002) 87, 1462 – 1469 ª 2002 Cancer Research UK All rights reserved 0007 – 0920/02 $25.00 www.bjcancer.com Nifedipine improves blood flow and oxygen supply, but not steady-state oxygenation of tumours in perfusion pressure- controlled isolated limb perfusion O Thews*,1, M Hummel1, DK Kelleher1, B Lecher1 and P Vaupel1 1Institute of Physiology and Pathophysiology, University of Mainz, Duesbergweg 6, 55099 Mainz, Germany Isolated limb perfusion allows the direct application of therapeutic agents to a tumour-bearing extremity. The present study investigated whether the dihydropyridine-type Ca2+-channel blocker nifedipine could improve blood flow and oxygenation status of experimental tumours during isolated limb perfusion. Perfusion was performed by cannulation of the femoral artery and vein in rats bearing DS-sarcoma on the hind foot dorsum. Perfusion rate was adjusted to maintain a perfusion pressure of 100 – 140 mmHg throughout the experiment. Following equilibration, nifedipine was continuously infused for 30 min (8.3 mg min71 kg71 BW). During constant-pressure isolated limb perfusion, nifedipine can significantly increase perfusion rate (+100%) and RBC flux (+60%) through experimental leg tumours. ‘Steal phenomena’ in favour of the surrounding normal tissue and oedema formation were not observed. Despite the increased oxygen availability (+63%) seen upon application of this calcium channel blocker, nifedipine does not result in a substantial reduction of tumour hypoxia, most probably due to an increase in O2 uptake with rising O2 supply to the tumour-bearing hind limb. Nifedipine application during isolated limb perfusion can enhance tumour microcirculation and may therefore promote the delivery (pharmacokinetics) of anti-cancer drugs to the tumour and by this improve the efficacy of pressure-controlled isolated limb perfusion. British Journal of Cancer (2002) 87, 1462 – 1469. doi:10.1038/sj.bjc.6600611 www.bjcancer.com ª 2002 Cancer Research UK Keywords: calcium channel blocker; isolated limb perfusion; nifedipine; tumour perfusion; tumour oxygenation; tumour vascular resistance Isolated limb perfusion (ILP) is a treatment modality for malignan- during growth which in turn is responsible for diffusion- and cies of the extremities in which the tumour-bearing limb is isolated perfusion-limited hypoxia resulting in a reduced efficacy of from the patient’s circulatory system and perfused separately. This oxygen-dependent agents (e.g., anthracyclines, cyclophosphamide procedure allows the administration of anti-cancer agents to the or melphalan; Vaupel et al, 2001). At the same time a poor and tumour at high doses with only a minimum risk of systemic toxi- inhomogeneous delivery of anti-cancer agents will diminish the city. High-dose regional chemotherapy was one of the first cytotoxic effect. For this reason, supportive treatment modalities concepts in ILP which was complemented more recently by the might be helpful which lead to an improvement or homogenisation application of cytokines and immune-modulators frequently in of tumour blood flow and/or a reduction of hypoxia already combination with hyperthermia (Omlor et al, 1995; Eggermont et present in many experimental or human tumours. Experimental Therapeutics al, 1996; Pisters et al, 1997; Schraffordt-Koops et al, 1998; Seyn- One group of drugs that might achieve these goals (and by this haeve et al, 2002). Since its introduction into the clinical setting might increase the efficacy of ILP) are calcium channel blockers (Creech et al, 1958), ILP with high-dose chemotherapy alone or (CCB). In experimental tumour therapy, CCBs have been of broad in combination with biological agents has been used for the treat- interest because of their ability to modify tumour blood flow and ment of loco-regionally advanced melanomas and locally advanced improve oxygenation status. soft tissue sarcomas not amenable to surgical resection (for a Blood flow modification following administration of these review see Hohenberger and Kettelhack, 1998). agents results from a dilation of resistance vessels and a reduction The response to chemo- or cytokine-therapy may however be in blood viscosity. Over the last two decades, CCBs (e.g., flunari- compromised by ‘biological’ factors such as tumour blood flow zine) have been shown to improve tumour blood flow, oxygen and microcirculation, tissue oxygenation or pH distribution. The availability (Kaelin et al, 1984; Vaupel and Menke, 1987, 1989), individual tumour microenvironment is a paramount determinant tumour oxygenation (Dewhirst et al, 1992) and to increase tumour in the outcome of non-surgical treatments (Vaupel et al, 1989; radiosensitivity (Hill and Stirling, 1987; Wood and Hirst, 1988, Ho¨ckel and Vaupel, 2001). For example, bulky tumours, which 1989). However, the proposed increase in tumour blood flow are an indication for ILP in sarcoma treatment, often show a resulting from a vasodilatation of vessels feeding the tumour is progressive deterioration and heterogeneity of tumour blood flow strongly dependent on the maintenance of a stable perfusion pres- sure which could not be achieved with all types of CCBs. This might however not be a problem in the case of the isolated perfu- *Correspondence: Dr O Thews; E-mail: [email protected] sion of tumour-bearing limbs by an extracorporeal circuit as Received 22 April 2002; revised 23 August 2002; accepted 30 August 2002 performed clinically, since perfusion pressure can be regulated by Nifedipine in isolated limb perfusion O Thews et al 1463 enhancing or lowering perfusate flow rate by means of an external Tumours were used when they reached a volume of between 0.8 pump. Thus, a CCB-induced drop in perfusion pressure could and 1.3 ml, 4 to 9 days after tumour implantation corresponding easily be compensated by an increase in the perfusion rate. Besides to a tumour mass of 0.5% of the body weight (Workman et al, their impact on the tumour oxygenation via an increase in the O2 1998). Tumours were implanted on both feet whereby one leg supply, CCBs also seem to be able to improve the O2 status directly was used for isolated limb perfusion and the contralateral leg as by reducing oxygen consumption (Biaglow et al, 1986; Vaupel and an additional control for the metabolic and bioenergetic para- Mueller-Klieser, 1986). meters. Studies had previously been approved by the regional In addition, CCBs show a chemosensitising effect (Helson, 1984) ethics committee and were conducted according to UKCCCR which is thought to be independent of effects on the classical slow guidelines (Workman et al, 1998) and to the German Law for inward calcium channel. The ability of verapamil and other CCBs Animal Protection. to reverse multi-drug resistance is linked to the interaction of the CCBs with the P-glycoprotein in the membrane of resistant Nifedipine tumour cells (Cornwell et al, 1987). The enhanced anti-tumour and anti-metastatic potential of cisplatin in combination with nife- Under protection from direct light, 2 mg nifedipine (Sigma, dipine in mice was attributed to the inhibition of tumour cell- Deisenhofen, Germany) was dissolved in 10 ml 96% ethanol. platelet aggregation and inhibition of platelet-enhanced tumour cell Further dilution was made with isotonic saline resulting in a adhesion to endothelial cells in vitro and in vivo by CCBs of the concentration of 0.1 mg ml71. This stock solution was added dihydropyridine type (Honn et al, 1985; Onoda et al, 1989). continuously at a rate of 0.5 ml h71 kg71 body weight (Harvard The present study investigated the possibility of using nifedipine infusion/withdrawal pump, Harvard, Edenbridge, UK) to the to improve perfusion and oxygenation status of experimental perfusion medium via a catheter placed in the femoral artery tumours during pressure-controlled ILP and thus to possibly resulting in a nifedipine dose of 8.3 mg nifedipine min71kg71 body enhance the efficacy of chemotherapy. Nifedipine was chosen weight. An equivalent volume of the vehicle was infused into rather than other CCBs since dihydropyridine derivatives preferen- control animals. tially block calcium channels in the plasma membrane of arterial smooth muscle cells rather than the myocardium and therefore Isolated limb perfusion function in contrast to other classes of CCBs predominantly as vasodilators (Jirtle, 1988; Robertson and Robertson, 1996), a prop- A single-pass ILP of the tumour-bearing extremity was performed erty which may be particularly suitable for increasing perfusion rate (in contrast to the earlier attempts of Nagel et al (1987) where a in a pressure-controlled system. closed blood circuit was used) using a perfusion system consisting of a peristaltic roller pump (mp13GJ-4, Ismatec, Zu¨rich, Switzer- land), a capillary oxygenator (SPS40002-P, Fresenius, Bad MATERIALS AND METHODS Homburg, Germany), a water-filled heat exchanger used to main- Animals and tumours tain a perfusate blood temperature of 36.5 to 37.58C, polyethylene cannulas and silicone tubing (Figure 1). The perfusion Male Sprague Dawley rats (Charles River Deutschland, Sulzfeld, medium was heparinised blood (20 i.u. ml71 whole blood) Germany; body weight 200 – 320 g) housed in our animal care obtained from donor rats. Prior to use, blood was diluted to a facility were used in this study. They received a standard diet haematocrit of 25% with bicarbonate-buffered oxypolygelatine and acidified water ad libitum. Experimental tumours were grown (55 g l71, Gelifundol, Biotest Pharma, Dreieich, Germany), an following subcutaneous injection of DS-ascites cells (0.4 ml; isotonic colloidal blood plasma substitute solution which is used approximately 104 cells per ml) into the dorsum of the hind foot. in the clinical setting. By using this drug for haemodilution an Experimental Therapeutics Figure 1 Experimental set-up for isolated limb perfusion in the rat. ª 2002 Cancer Research UK British Journal of Cancer (2002) 87(12), 1462 – 1469 Nifedipine in isolated limb perfusion O Thews et al 1464 isotonic and isooncotic perfusate was obtained. Mean haemoglobin monitoring period to optimise probe positioning, minimise tissue concentration (cHb) was 77 g l71.

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