LETTERS
TO
Thérapie 2014 Novembre-Décembre; 69 (6): 533–534 DOI: 10.2515/therapie/2014208
EDITOR
© 2014 Société Française de Pharmacologie et de Thérapeutique
Targeting Solid Tumours With Potassium Channel Activators. A Return to Fundamentals? Philippe Trechot Department of Clinical Pharmacology, University Hospital, Nancy, France Text received April 3rd, 2014; accepted September 24th, 2014 Abstract – From a pharmacological point of view nicotinamide and minoxidil are potassium channel activators. Nicotinamide is used as a radiosensitizer in ARCON (accelerated radiotherapy combined with carbogen breathing and nicotinamide) therapeutic strategy with promising results but not confirmed so far. Minoxidil has never been considered by radiotherapists. Based from recent pathophysiological considerations we suggest a new perspective for the use of these two “old” molecules in order to target solid tumours. Keywords: nicotinamide; minoxidil; radiosensitizer; solid tumours Résumé – Utilisation des activateurs des canaux potassiques pour cibler les tumeurs solides. Un retour aux fondamentaux ? Sur un plan pharmacologique, le nicotinamide et le minoxidil sont des activateurs des canaux potassiques. Le nicotinamide est un médicament utilisé comme radiosensibilisant dans le protocole ARCON (accelerated radiotherapy combined with carbogen breathing and nicotinamide) avec des résultats intéressants, mais non confirmés à ce jour, tandis que le minoxidil n’a jamais été envisagé par les radiothérapeutes dans cette indication. Sur la base de notions physiopathologiques récentes nous proposons, dans le but de cibler les tumeurs solides, un nouvel abord quant à l’utilisation de ces deux « vieilles » molécules. Mots clés : nicotinamide ; minoxidil ; radiosensibilisant ; tumeurs solides Abreviations: see end of article.
1. Introduction Many chemotherapeutic agents enhance the toxicity of radiotherapy when the two modalities are combined. They are not considered to be true radiosensitizer, as they generally affect some degree of anti-tumour when administrated as single agents.
A pure radiosensitizer is a drug, a modality of therapy or an intervention that, on its own, lacks direct anti-tumour activity but enhances the cytotoxicity of radiotherapy when employed in combination.[1] One of the earliest pure radiosensitizer was oxygen. Since then, carbogen, a mixture of oxygen and carbon dioxide (95% O2 +5% CO2), has been used in combination with agents like nicotinamide which enhance tumour blood flow, thus inducing a synergistic effect. ARCON (accelerated radiotherapy combined with carbogen breathing and nicotinamide) is a “therapeutic strategy” that combines radiation treatment with nicotinamide and inhalation of hyperoxic gas to decrease perfusion-limited hypoxia.[2] Today, nicotinamide is an “old dog radiosensitizer” that is struggling to dismantle its potential, while minoxidil has never been considered by radiotherapists despite interesting pharmacological properties.
2. Nicotinamide This vasoactive agent has been extensively studied as a drug that actively reduces transient hypoxia caused by temporary vascular shutdown, reducing those areas of the tumour which are underperfused and thus hypoxic.[3] Tested in animals, then extrapolated to humans as a substance that fights against hypoxia in solid tumours (STs) to improve oxygen status, nicotinamide alone can enhance radiosensitivity but achieves maximal enhancement when used (3 to 12 g oral daily dose) with (and before) carbogen breathing. However, in clinical practice, a perfect match between nicotinamide and carbogen breathing is difficult with regard to its peak plasma concentration and timing.[4] Promising results with ARCON were obtained but not confirmed: the potential of ARCON should therefore be explored further.[5] Some reasons can be proposed to explain these negative results: i) transient hypoxia is not a cause of local failure after radiotherapy; ii) the brief and brutal bioavailability of nicotinamide is responsible for STs being underexposed to the pharmacological action of this chemical. Recent data on nicorandil, a nicotinamide ester [N-(2-hydroxyethyl) nicotinamide-nitrate ester], confirms that nicotinamide is an ST radiosensitizer that exhibits indirect angiogenic activity by promoting the growth of capillaries, but which is also associated or linked to the properties of potassium channel activators (PCAs), inducing vasodilatation by opening membrane-bound adenosine triphosphate-dependent potassium channels (ATP-dependent K+ channels).[6] Indeed, this property is one of the steps required for nicorandil-induced ulcerations, which are typically localised in areas of trauma.[7, 8] To avoid pharmacological ST underexposure to nicotinamide, we suggest niacin, a precursor of active nicotinamide.[9, 10] The use of niacin before and during radiotherapy could promote the
Article publié par EDP Sciences
534
Trechot
Tableau I. Mean plasma nicotinamide pharmacokinetic parameters.
Nicotinamide Drug dose C max t max t ½ AUC 0 → ∞ ref (origin) (g) (μg/mL) (h) (h) (μg/h.mL) Nicotinamide 3 70 0.5 5.9 29.2 [9] (as is) Nicotinamide (from niacin 2 2 8.6 4.3 21.6 [10] extended release) AUC: area under curve; Cmax: peak plasma concentration
long-lasting exposure of STs to PCAs (table I). Furthermore, this method would limit the “peak plasma concentration and timing” problem as well as large inter-patient variations, severe adverse effects and decreased compliance related to high doses of nicotinamide.[11]
nicotinamide, niacin and minoxidil (doses to be determined) would allow the refuting or confirming of this pharmacological hypothesis. Conflicts of interests. None. Abbreviations. ARCON: accelerated radiotherapy combined with carbogen breathing and nicotinamide; ATP-dependent K+ channels: adenosine triphosphate-dependent potassium channels; PCAs: potassium channel activators; STs: solid tumours.
References 1.
2.
3. Minoxidil 2,6-diamino-4-piperidino-pyrimidine1-oxide, another PCA, may be of similar interest. It is an antihypertensive that is used topically to stimulate hair growth in cases of alopecia. The plasma half-life of one oral dose is about 4.2 hours, but the haemodynamic effect persists for up to 75 hours, probably due to accumulation at the site of action. Opening of potassium channels by minoxidil sulphate (the active form of the drug) induces peripheral vasodilatation by direct action on vascular smooth muscle, and also appears to be responsible for the stimulation of hair growth.[12] In 1995, Brenda et al.[13] compared the ability of four topical drugs, including minoxidil, to promote the healing of open wounds in rats, and found, on the 49th post-operative day, that wounds in the minoxidil group showed “a small amount of inflammatory infiltrate located only under the raw area, and the presence of an extensive band of a new epithelium, adhering to the subjacent granulation tissue”. They concluded that minoxidil acts directly on the arterioles, and that “the mechanism whereby minoxidil increases epithelial proliferation may therefore be related to increased blood flow in the tissues at the edge of the raw area”.
4. Conclusion With the experience acquired on the follow-up activity of radiosensitizer, the use of certain molecules, which are currently pharmacologically better known, could avoid some past wanderings. In addition, these “old” molecules are of a reasonable cost and their adverse side effects have already been recognised under conditions of everyday use. A preliminary study in animal models comparing
© Société Française de Pharmacologie et de Thérapeutique
3.
4.
5.
6. 7.
8. 9.
10.
11.
12. 13.
Brade AM, Allibhai Z. In: Radiation sensitizers. Advances in radiation oncology in lung cancer 2001: 213-9. Jeremic B (ed) Springer-Verlag Berlin Heidelberg 2011 Kaanders J, Bussink J, van der Kogel AJ. ARCON: a novel biology-based approach in radiotherapy. Lancet Oncol 2002; 3: 728-37 Horsman MR, Chaplin DJ, Brown JM. Tumor radiosensitization by nicotinamide: a result of improved perfusion and oxygenation. Radiat Res 1989; 118: 139-50 Horsman MR, Siemann DW, Chaplin DJ, et al. Nicotinamide as a radiosensitizer in tumours and normal tissues: the importance of drug dose and timing. Radiother Oncol 1997; 45: 167-74 Janssens GO, Rademakers SE, Terhaard CH, et al. Improved recurrence-free survival with ARCON for anemic patients with laryngeal cancer. Clin Cancer Res 2014; 20: 1345-54 Patel GK, Harding KG. Nicorandil ulcer: moves beyond the mucosa. Ann R Coll Surg Engl 2010; 92: 451-2 Trechot P, Barbaud A, Petitpain N, et al. Nicorandil and ulcerations: a NAD/ NADP and nicotinic acid-dependent side-effect? Br J Dermatol 2008; 158: 1150-1 Trechot P, Claeys A, Petitpain N, et al. Nicorandil and ulcerations: the Trojan horse? J Eur Acad Dermatol Venereol 2012; 26: 925-6 Horsman MR, Hoyer M, Honess DJ, et al. Nicotinamide pharmacokinetics in humans and mice: a comparative assessment and the implications for radiotherapy. Radiother Oncol 1993; 27: 131-9 Menon RM, Adams MH, Gonzalez MA, et al. Plasma and urine pharmacokinetics of niacin an its metabolites from an extended-release niacin formulation. Int J Clin Phamacol Ther 2007; 45: 448-54 Kaanders J, Startford M, Liefers J, et al. Administration of nicotinamide during a five-to seven-week course of radiotherapy: pharmacokinetics, tolerance, and compliance. Radiother Oncol 1997; 43: 67-73 Sweetman SC. Minoxidil. In: Martindale. The complete drug reference, 37th edn. London: Pharmaceutical Press, 2011: 1474-5 Brenda E, Marques A, Saldiva PHN, et al. Action of papain, sugar, minoxidil, and glucan on excisional wounds in rats. Curr Ther Res 1995; 56(12) : 1285-97 DOI: http://dx.doi.org/10.1016/0011-393X(95)85073-2
Correspondence and offprints: Philippe Tréchot, Department of Clinical Pharmacology, University Hospital, 54035 Nancy, France E-mail: [email protected]
Thérapie 2014 Novembre-Décembre; 69 (6)
TO
Thérapie 2014 Novembre-Décembre; 69 (6): 533–534 DOI: 10.2515/therapie/2014208
EDITOR
© 2014 Société Française de Pharmacologie et de Thérapeutique
Targeting Solid Tumours With Potassium Channel Activators. A Return to Fundamentals? Philippe Trechot Department of Clinical Pharmacology, University Hospital, Nancy, France Text received April 3rd, 2014; accepted September 24th, 2014 Abstract – From a pharmacological point of view nicotinamide and minoxidil are potassium channel activators. Nicotinamide is used as a radiosensitizer in ARCON (accelerated radiotherapy combined with carbogen breathing and nicotinamide) therapeutic strategy with promising results but not confirmed so far. Minoxidil has never been considered by radiotherapists. Based from recent pathophysiological considerations we suggest a new perspective for the use of these two “old” molecules in order to target solid tumours. Keywords: nicotinamide; minoxidil; radiosensitizer; solid tumours Résumé – Utilisation des activateurs des canaux potassiques pour cibler les tumeurs solides. Un retour aux fondamentaux ? Sur un plan pharmacologique, le nicotinamide et le minoxidil sont des activateurs des canaux potassiques. Le nicotinamide est un médicament utilisé comme radiosensibilisant dans le protocole ARCON (accelerated radiotherapy combined with carbogen breathing and nicotinamide) avec des résultats intéressants, mais non confirmés à ce jour, tandis que le minoxidil n’a jamais été envisagé par les radiothérapeutes dans cette indication. Sur la base de notions physiopathologiques récentes nous proposons, dans le but de cibler les tumeurs solides, un nouvel abord quant à l’utilisation de ces deux « vieilles » molécules. Mots clés : nicotinamide ; minoxidil ; radiosensibilisant ; tumeurs solides Abreviations: see end of article.
1. Introduction Many chemotherapeutic agents enhance the toxicity of radiotherapy when the two modalities are combined. They are not considered to be true radiosensitizer, as they generally affect some degree of anti-tumour when administrated as single agents.
A pure radiosensitizer is a drug, a modality of therapy or an intervention that, on its own, lacks direct anti-tumour activity but enhances the cytotoxicity of radiotherapy when employed in combination.[1] One of the earliest pure radiosensitizer was oxygen. Since then, carbogen, a mixture of oxygen and carbon dioxide (95% O2 +5% CO2), has been used in combination with agents like nicotinamide which enhance tumour blood flow, thus inducing a synergistic effect. ARCON (accelerated radiotherapy combined with carbogen breathing and nicotinamide) is a “therapeutic strategy” that combines radiation treatment with nicotinamide and inhalation of hyperoxic gas to decrease perfusion-limited hypoxia.[2] Today, nicotinamide is an “old dog radiosensitizer” that is struggling to dismantle its potential, while minoxidil has never been considered by radiotherapists despite interesting pharmacological properties.
2. Nicotinamide This vasoactive agent has been extensively studied as a drug that actively reduces transient hypoxia caused by temporary vascular shutdown, reducing those areas of the tumour which are underperfused and thus hypoxic.[3] Tested in animals, then extrapolated to humans as a substance that fights against hypoxia in solid tumours (STs) to improve oxygen status, nicotinamide alone can enhance radiosensitivity but achieves maximal enhancement when used (3 to 12 g oral daily dose) with (and before) carbogen breathing. However, in clinical practice, a perfect match between nicotinamide and carbogen breathing is difficult with regard to its peak plasma concentration and timing.[4] Promising results with ARCON were obtained but not confirmed: the potential of ARCON should therefore be explored further.[5] Some reasons can be proposed to explain these negative results: i) transient hypoxia is not a cause of local failure after radiotherapy; ii) the brief and brutal bioavailability of nicotinamide is responsible for STs being underexposed to the pharmacological action of this chemical. Recent data on nicorandil, a nicotinamide ester [N-(2-hydroxyethyl) nicotinamide-nitrate ester], confirms that nicotinamide is an ST radiosensitizer that exhibits indirect angiogenic activity by promoting the growth of capillaries, but which is also associated or linked to the properties of potassium channel activators (PCAs), inducing vasodilatation by opening membrane-bound adenosine triphosphate-dependent potassium channels (ATP-dependent K+ channels).[6] Indeed, this property is one of the steps required for nicorandil-induced ulcerations, which are typically localised in areas of trauma.[7, 8] To avoid pharmacological ST underexposure to nicotinamide, we suggest niacin, a precursor of active nicotinamide.[9, 10] The use of niacin before and during radiotherapy could promote the
Article publié par EDP Sciences
534
Trechot
Tableau I. Mean plasma nicotinamide pharmacokinetic parameters.
Nicotinamide Drug dose C max t max t ½ AUC 0 → ∞ ref (origin) (g) (μg/mL) (h) (h) (μg/h.mL) Nicotinamide 3 70 0.5 5.9 29.2 [9] (as is) Nicotinamide (from niacin 2 2 8.6 4.3 21.6 [10] extended release) AUC: area under curve; Cmax: peak plasma concentration
long-lasting exposure of STs to PCAs (table I). Furthermore, this method would limit the “peak plasma concentration and timing” problem as well as large inter-patient variations, severe adverse effects and decreased compliance related to high doses of nicotinamide.[11]
nicotinamide, niacin and minoxidil (doses to be determined) would allow the refuting or confirming of this pharmacological hypothesis. Conflicts of interests. None. Abbreviations. ARCON: accelerated radiotherapy combined with carbogen breathing and nicotinamide; ATP-dependent K+ channels: adenosine triphosphate-dependent potassium channels; PCAs: potassium channel activators; STs: solid tumours.
References 1.
2.
3. Minoxidil 2,6-diamino-4-piperidino-pyrimidine1-oxide, another PCA, may be of similar interest. It is an antihypertensive that is used topically to stimulate hair growth in cases of alopecia. The plasma half-life of one oral dose is about 4.2 hours, but the haemodynamic effect persists for up to 75 hours, probably due to accumulation at the site of action. Opening of potassium channels by minoxidil sulphate (the active form of the drug) induces peripheral vasodilatation by direct action on vascular smooth muscle, and also appears to be responsible for the stimulation of hair growth.[12] In 1995, Brenda et al.[13] compared the ability of four topical drugs, including minoxidil, to promote the healing of open wounds in rats, and found, on the 49th post-operative day, that wounds in the minoxidil group showed “a small amount of inflammatory infiltrate located only under the raw area, and the presence of an extensive band of a new epithelium, adhering to the subjacent granulation tissue”. They concluded that minoxidil acts directly on the arterioles, and that “the mechanism whereby minoxidil increases epithelial proliferation may therefore be related to increased blood flow in the tissues at the edge of the raw area”.
4. Conclusion With the experience acquired on the follow-up activity of radiosensitizer, the use of certain molecules, which are currently pharmacologically better known, could avoid some past wanderings. In addition, these “old” molecules are of a reasonable cost and their adverse side effects have already been recognised under conditions of everyday use. A preliminary study in animal models comparing
© Société Française de Pharmacologie et de Thérapeutique
3.
4.
5.
6. 7.
8. 9.
10.
11.
12. 13.
Brade AM, Allibhai Z. In: Radiation sensitizers. Advances in radiation oncology in lung cancer 2001: 213-9. Jeremic B (ed) Springer-Verlag Berlin Heidelberg 2011 Kaanders J, Bussink J, van der Kogel AJ. ARCON: a novel biology-based approach in radiotherapy. Lancet Oncol 2002; 3: 728-37 Horsman MR, Chaplin DJ, Brown JM. Tumor radiosensitization by nicotinamide: a result of improved perfusion and oxygenation. Radiat Res 1989; 118: 139-50 Horsman MR, Siemann DW, Chaplin DJ, et al. Nicotinamide as a radiosensitizer in tumours and normal tissues: the importance of drug dose and timing. Radiother Oncol 1997; 45: 167-74 Janssens GO, Rademakers SE, Terhaard CH, et al. Improved recurrence-free survival with ARCON for anemic patients with laryngeal cancer. Clin Cancer Res 2014; 20: 1345-54 Patel GK, Harding KG. Nicorandil ulcer: moves beyond the mucosa. Ann R Coll Surg Engl 2010; 92: 451-2 Trechot P, Barbaud A, Petitpain N, et al. Nicorandil and ulcerations: a NAD/ NADP and nicotinic acid-dependent side-effect? Br J Dermatol 2008; 158: 1150-1 Trechot P, Claeys A, Petitpain N, et al. Nicorandil and ulcerations: the Trojan horse? J Eur Acad Dermatol Venereol 2012; 26: 925-6 Horsman MR, Hoyer M, Honess DJ, et al. Nicotinamide pharmacokinetics in humans and mice: a comparative assessment and the implications for radiotherapy. Radiother Oncol 1993; 27: 131-9 Menon RM, Adams MH, Gonzalez MA, et al. Plasma and urine pharmacokinetics of niacin an its metabolites from an extended-release niacin formulation. Int J Clin Phamacol Ther 2007; 45: 448-54 Kaanders J, Startford M, Liefers J, et al. Administration of nicotinamide during a five-to seven-week course of radiotherapy: pharmacokinetics, tolerance, and compliance. Radiother Oncol 1997; 43: 67-73 Sweetman SC. Minoxidil. In: Martindale. The complete drug reference, 37th edn. London: Pharmaceutical Press, 2011: 1474-5 Brenda E, Marques A, Saldiva PHN, et al. Action of papain, sugar, minoxidil, and glucan on excisional wounds in rats. Curr Ther Res 1995; 56(12) : 1285-97 DOI: http://dx.doi.org/10.1016/0011-393X(95)85073-2
Correspondence and offprints: Philippe Tréchot, Department of Clinical Pharmacology, University Hospital, 54035 Nancy, France E-mail: [email protected]
Thérapie 2014 Novembre-Décembre; 69 (6)
