In the 1930s, Warburg noted ‘the remarkable ex-tent to which living tumour cells are able to con-vert carbohydrate into lactic acid’1. Subsequently,for about 50 years, it was assumed that tumourcells would have an acidic intracellular pH (pHi).Microelectrode measurements of tumour pH ap-peared to confirm that the pH of tumour cells waslow. However, when 31P magnetic resonancespectroscopy (MRS) was introduced for the studyof tumours in situ2, it provided a simple, non-invasive means of estimating pHi, and tumourcells turned out to have neutral or slightly alkalinepHi values3. Like normal cells, tumour cells regu-late their cytoplasmic pHi within a narrow rangeto provide a favourable environment for variousintracellular activities. Indeed, many tumour cellshave a high pHi, which is considered to be per-missive for cell growth4. In tumours, it is the ex-tracellular fluid that is relatively acid. It was mainlythis compartment that the microelectrodes hadbeen sampling, and such measurements are nowacknowledged largely to reflect extracellular pH(pHe ). The result is a reverse or negative pH gra-dient (pHi . pHe) across the tumour-cell plasmamembrane in situ compared with normal tissueswhere pHi (~7.2) is lower than pHe (~7.4) (Ref 5).

pH measurement by MRSpHiThe MRS measurement of pHi is based on a pH-dependent chemical shift difference betweenthe 31P inorganic phosphate (Pi) signal and an

endogenous reference signal. At physiologicalpH, the position of the Pi signal reflects the rela-tive concentrations of the two phosphate species(H2PO4

2 and HPO422) present. There is phos-

phate in both the intra- and extracellular com-partments, so unless two Pi peaks can be re-solved in the MRS spectrum, the MRSmeasurement of tissue pH is a weighted averageof pHi and pHe. In normal tissue, the concentrationof intra- and extracellular Pi is approximately thesame. It is generally considered that the pHmeasured by MRS is intracellular because the ex-tracellular volume, for example of liver, is lessthan 25% of the total cell volume and thus extra-cellular Pi is only a minor component. For tu-mours, however, this assumption might not applybecause, in addition to having higher-than-normalPi signals, their extracellular volume could also be high, owing to necrotic areas and cysts for example. Estimates of the proportion of Pi signalcoming from the intracellular volume can bemade if the total tumour volume and the fractionalvolume of extracellular water are known.Calculations show that if the extracellular volumedoes not exceed 55% then pH measured by MRSlargely represents pHi (Ref. 5).

pHeRecently, several MR-specific extracellular mark-ers for pHe have become available6,7 that allowthe simultaneous measurement of pHi and pHe intumours and normal tissue. Studies using these

probes confirm that tumour pHe in many (but notall) animal models is lower than pHi. However, itshould be noted that pHe comprises both the in-terstitial and vascular compartments, and the lat-ter (pHb) usually has a pH of about 7.4.

Why do tumours have high rates ofglycolysis?

Many tumours have high rates of glycolysis, re-gardless of whether their supply of oxygen isgood (Warburg’s original observation) or poor.Most tumours in vivo synthesize some ATP by oxidative metabolism, and some by glycolyticmetabolism to lactate (aerobic glycolysis).Clearly, if the oxygen supply is removed (acutehypoxia), the tumour cells switch to anaerobic gly-colysis, just as would normal tissue. Research onhepatomas has shown that the rate of tumour gly-colysis appears to be associated with the differ-entiation status and growth rate of the tumour8.But the question as to why some of the energydemand is satisfied by aerobic glycolysis, ratherthan by mitochondrial oxidative phosphorylation,remains unanswered. Several normal cell-typesthat are not necessarily hypoxic (for example,leukocytes and enterocytes) also have high ratesof glycolysis and produce lactic acid. Leukocytes,after many rounds of cell division, have fewermitochondria than their stem-cell precursors, andsome tumour cells contain about half the mito-chondria of comparable, untransformed tissue. Ifthere are not enough mitochondria to replace ATP

151357-4310/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S1357-4310(99)01615-9

OpinionMOLECULAR MEDICINE TODAY, JANUARY 2000 (VOL. 6)

Causes and consequences oftumour acidity andimplications for treatment

Marion Stubbs, Paul M.J. McSheehy, John R. Griffiths and C. Lindsay Bashford

Tumour cells have a lower extracellular pH (pH e ) than normal cells; this is an intrinsic feature of thetumour phenotype, caused by alterations either in acid export from the tumour cells or in clearance ofextracellular acid. Low pH e benefits tumour cells because it promotes invasiveness, whereas a highintracellular pH (pH i ) gives them a competitive advantage over normal cells for growth. Molecular geneticapproaches have revealed hypoxia-induced coordinated upregulation of glycolysis, a potentially importantmechanism for establishing the metabolic phenotype of tumours. Understanding tumour acidity opens upnew opportunities for therapy.

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Opinion MOLECULAR MEDICINE TODAY, JANUARY 2000 (VOL. 6)

at the required rate, enhanced glycolysis wouldbe an obvious metabolic solution, and many tu-mour cells appear to adopt a mixed metaboliceconomy of simultaneous oxidative phosphoryl-ation and glycolysis. In most normal cells, the lev-els of ADP and Pi needed to sustain a high gly-colytic rate would be sufficient to maximallyactivate oxidative phosphorylation. The changesin metabolic control that allow both pathways tobe active, but not saturated, in tumours (and mitochondrially deficient normal cells) remain uncertain. The observation that overexpressionof key glycolytic enzymes in yeast abolishes thePasteur effect 9 might suggest that the oncogenicevents that switch on uncontrolled DNA repli-cation in the nucleus fail to cause an equivalentincrease in replication of mitochondrial DNA, andpermit overexpression of glycolytic enzymes.

How might the activities of theenzymes participating in glycolysis be

raised?Modern metabolic control analysis has shown thatthe control of metabolic pathways is distributedover many enzymes; if glycolytic flux is increased,many of the glycolytic enzymes are likely to haveraised activities10. Recently, a widespread systemof oxygen-related gene expression, based on theactivation of the transcription factor hypoxia inducible factor-1 (HIF-1), has been defined11.Intriguingly, these molecular genetic approaches

have revealed that sequences that are 59 to thecoding region of genes for glycolytic enzymescontain a common motif12, and this could providethe basis for coordinated upregulation of the path-way. Chronic hypoxia also upregulates the ex-pression of a number of ‘stress’ proteins, severalof which are glycolytic enzymes. For example, themajor hypoxic stress protein p34 is an isozyme oflactate dehydrogenase. These findings suggestthat hypoxia is a trigger that coordinates inductionof gene expression and may well be one of thefactors that determines the metabolic phenotypeof tumours. Thus, it is possible to imagine that thegenetic disruptions that produce tumour cellsmight also stimulate the HIF-1 system without theneed for the hypoxic stimulus. Indeed, HIF-1 is activated constitutively in cells that are defectivein an important tumour suppressor, the vonHippel–Lindau gene product13. The modified cellswould have the metabolic phenotype associatedwith tumours and could induce the chaotic vascu-lature typically found in tumours. Subsequent hy-poxia would reinforce this pattern by super-induc-tion of the HIF-1 system12.

Why is pHe of tumours acidic?Does excess lactate production causeextracellular acidity?Following glycolysis, the major pathway of lactateexport from cells is the H1-monocarboxylate co-transporter. The steady-state intracellular lactate

concentration of tumour cells tends to be at leasttwofold higher than the extracellular concen-tration. This follows from the intimate associationbetween lactate and H1 gradients and the direc-tion of the H1 gradient across the tumour-cellplasma membrane14. One obvious hypothesis toexplain the low pHe in solid tumours is that meta-bolic acids (lactate and/or CO2) exported from thecancer cells into the interstitial fluid cannot be ex-ported to the blood rapidly enough. This poor H1

clearance could be due to the disorganized vas-culature of tumours, poor lymphatic drainage andelevated interstitial pressure. However, when acancer cell line that produced large amounts oflactic acid was compared with a mutant line thathad a defective glycolytic pathway and producedvery small amounts of lactic acid, solid tumoursgrown up from both the wild-type and mutant linesstill had an acidic interstitial pH (Ref. 15). Onepossible explanation for this is that the mutantcells had produced large amounts of CO2 by oxi-dative metabolism, which would also acidify theextracellular compartment. However, other mu-tants defective in the glycolytic pathway producedsimilar amounts of CO2 to the normal cells. Thisimplies that the acidity of tumours is not causedsimply by excessive production of lactate andCO2 (Ref. 16).

Does changing the set point of pHiregulation cause extracellular acidity?Tumour cells might raise their set point for pHi byincreasing the export of H1 from the intracellularcompartment4. Increased H1 export could permitfaster overall production of acid by tumour metab-olism (‘H1 source’ in Fig.1) and lead indirectly toincreased extracellular acidity. The increased H1

export could be achieved via activation of the mi-togen-sensitive Na1/H1exchanger, or via in-creased functional expression in the plasmamembrane of H1-pumping ATPases. Functionalexpression of H1-pumping ATPases has beenmeasured on the cell surface of some tumourcells, particularly those with a higher pHi, and it isassociated with greater ATP turnover, increasedglycolysis and decreased protein degradation4, allfeatures of the tumour metabolic phenotype .

Is pHe regulated and does changing theset point of pHe cause extracellularacidity?The pH of any compartment at steady-state is de-termined by the balance between H1 entering andleaving that compartment (Fig.1) and the natureof the internal buffers. pHi and pHe correlatestrongly in cell culture experiments in which thepH of the medium has been manipulated.However in four rodent models of solid tumours(including one human xenograft ) in which pHi

Figure 1. Factors affecting pHi and pHe in normal and tumour tissue. H1 produced by metabolism is pumpedfrom the intracellular compartment into the interstitial compartment and subsequently flows into the blood. Theconcentration of H1 in the interstitial compartment is relatively high in tumours (low pHe ) compared with nor-mal tissue. At steady state, the flow (f) of H1 between the compartments is equal (f1 5 f2). The increased in-terstitial acidity of tumour cells could be caused by (a) an increase in H1 pumping by, for example, expres-sion in the plasma membrane of vacuolar-type H1 pumps or (b) an increase in resistance induced either byaltered gene expression or by the action of cytokines on cells at the interstitial/vascular interface.

(b)

(a)

IntracellularH+ source

pH

6

7

8

H+ pump

pHe ~6.8

pHi ~7.2 BloodH+ sink

pHb ~7.4pHe ~7.3

Tumour

ExtracellularH+ store

Normalf1

f2

Molecular Medicine Today

and pHe were measured simultaneously in vivo(using 3-aminopropylphosphonate6 or ZK150471(Ref. 7) as extracellular pH markers), only onemodel (a xenograft of human HT29 cells)showed a correlation between pHi and pHe,whereas the other three models (transplanted rodent tumours) showed no correlation betweenthese two parameters14. Does this simply reflecta higher output of hydrogen ions by the HT29cells or is there usually regulation of pH in the ex-tracellular space that is somehow subverted bythe tumour cell?

If, like pHi, tumour pHe is regulated, any corre-lation between these two parameters would de-pend on factors other than pHi, as was observedin the three rodent tumour models. Under these cir-cumstances, the acidic pHe of tumours could be aconsequence of some interaction between the tu-mour cell and its host-cell matrix. For example, theset point for pHe might be altered at the intersti-

tial–vascular interface (Figs 1 and 2); tumour en-dothelial cells are known to release growth factorsand cytokines that regulate tumour cell functionand vice versa17. Human cytokines released bythe HT29 xenograft might have been unable tomodulate the host (rodent) stromal cells.

Is low pHe an intrinsic feature of thecancer phenotype?

These considerations imply that acidic pHe, a fea-ture of tumours that has been proposed to facili-tate tumour progression18, might not be just aconsequence of tumour metabolism, but an in-trinsic tumour property. For example, tumour cellsmight change their pHe set point either as a resultof tumour gene-expression, for example by over-expression of carbonic anhydrase isozymescaused by inactivation of the VHL tumour sup-pressor gene19, or as a result of a tumourcell–host-matrix interaction. Low pHe has been

associated with tumourigenic transformation,chromosomal rearrangements, extracellular ma-trix breakdown, migration and invasion, inductionof the expression of cell growth factors and pro-teases, and it is a prominent feature of a reac-tion–diffusion model of cancer invasion18.Characteristics of the cancer phenotype mightalso reduce the viability of adjacent normal hostcells.

Consequences of tumour acidityOne consequence of metabolism in any tissue isthe formation of H1, which must be removed fromthe cell if the internal milieu is to maintain its nor-mal pH. In cancer cells, the H1 formed during glycolysis leaves the cell with lactate2, via the

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OpinionMOLECULAR MEDICINE TODAY, JANUARY 2000 (VOL. 6)

Figure 2. Mechanisms involved in maintenance of intracellular neutrality in tumours. When lactic acid is pro-duced from glucose (a non-electrolyte), the lactate ion and H1 can pass into the extracellular fluid via themonocarboxylate carrier (a). Some lactate ions accumulate in the cell and contribute to the high lactate lev-els commonly observed in tumours. The Na1/H1 antiport (b), which is activated in transformed cells, exportsH1 and imports Na1 contributing to the high intracellular Na1, another common tumour-cell feature. There isalso some buffering by HCO3

2, which enters the cell by the Na1 dependent HCO32 /Cl2exchanger (c). There

are many additional mechanisms which may also play a role in the regulation of maintenance of neutral pHi

including the ATP-dependent Na1/K1 antiport (d) and vacuolar H1-pump (e). The low energy of the Na1 gra-dient causes Ca21 to accumulate (f) and together with high Pi may initiate tumour calcification . Also shownis a hypothetical exchanger at the tumour–endothelial cell interface (g) which might regulate pHe.

Tumour cellplasma membrane

Lactate−

H+

H+

H+Cl−

HCO3−

?

?

Na+Na+

Ca2+

Na+

K+

ATP

ADP+Pi

Endothelial cells

ATP

ADP+Pi

(a)

(b)

(c)

(g)

(d)

(e)

(f)

Glycolysis

Glucose

pHi ~7.2

pHe ~6.8

pHb ~7.4

Molecular Medicine Today

GlossaryCalcification – The deposition of calciumsalts in tissue.

Chemical shift – A shift in resonating fre-quency between molecules that dependson the electron shielding of their chemicalbonds. For example, HPO4

22 resonates ata slightly different frequency to that ofHPO4

2.

Cytokines – Locally produced proteinsthat regulate the differentiation, prolifer-ation and activities of cells.

Glycolysis – The sequence of metabolicreactions that transforms glucose intopyruvic acid with the concomitant for-mation of two molecules of ATP from ADPand Pi. Pyruvic acid is subsequently con-verted to CO2 and water in the mitochon-dria, or to lactic acid in the cytosol.

HIF-1 (hypoxia inducible factor-1) – Atranscription factor that can bind to hy-poxia response elements and activategene transcription. It has been implicatedin, for example, the regulation of angio-genesis, glucose transport, glucosemetabolism and nitric oxide metabolism.

Pasteur effect – The inhibition of glycol-ysis by respiration.

Phenotype – The observable character-istics of cells which are the outcome ofthe interaction between cellular genes(the genotype) and the environment.

Xenograft – A graft of living tissue froman animal of one species (e.g. man) intothat of a different species (e.g. mouse).

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Opinion MOLECULAR MEDICINE TODAY, JANUARY 2000 (VOL. 6)

monocarboxylate/ H1 co-transporter. In addition,H1 is exported by the Na1/H1 antiporter, using theenergy of the Na1 gradient. This antiporter, whichis activated in tumour cells, elevates cytosolicNa1, which will subsequently be pumped out bythe (ATP-driven) Na1/K1 ATPase. H1 might alsobe exported by vacuolar type H1 ATPases in theplasma membrane.

Adecreased Na1 gradient provides less energyfor Na1/Ca21 exchange, which could lead to an accumulation of intracellular Ca21. Pi is also in-creased20 (tumour cells have a lower energy cur-rency than normal tissues, caused in part by theelevated ion pumping), and disruption of bothCa21 and Pi metabolism might trigger tumour

calcification , especially if pHi remains slightly al-kaline. Tumour calcification is a common featureof tumour pathology, forming the basis of diag-nostic tests for cancer, most notably mammogra-phy. Dystrophic calcification is also seen in manyother chronically injured tissues, such as scarsfrom myocardial infarction, the common link beinghypoxia leading to alterations in ion distribution.

What are the implications of tumourextracellular acidity for treatment?

Tumour pH gradients have practical importancebecause most anticancer drugs must be trans-ported either by active transport or by passive dif-fusion into cells, where they frequently undergofurther metabolism. As all of these processesmight be pH sensitive, the cytotoxic activity of an-ticancer drugs could depend on both pHi and pHe.In particular, drugs that are weak electrolytesenter cells by passive diffusion of the non-ionizedform of the compound. Such drugs will tend topartition preferentially across the cell membraneinto the compartment where their ionized formpredominates. Thus, for example, primaryamines tend to be excluded from, and carboxylicacids accumulated by, the more alkaline intracel-lular compartment21 (Fig. 3). In addition, the tox-icity of a number of drugs is sensitive to variationin pH as a result of various mechanisms that arenot dependent on ionization-dependent diffusionthrough the cell membrane. For example, mel-phalan toxicity is enhanced by pHe modificationwithout increased uptake or accumulation, andthe accumulation of weakly acidic 5-fluorouracil

(5FU) is pH-dependent even though its pK liesoutside the physiological range22.

Methods and consequences ofmodifying tumour pH in vivo

Various strategies for altering pHi and pHe havebeen tried in the quest for new anticancer strat-egies for solid tumours. In this article, only tu-mours in the steady state have been considered.However, in an acute situation, changes in pH canbe induced in vivo; for instance, hyperglycaemiaalters tumour pHi and pHe, resulting in an increasein DpH, which increases retention of 5FU. As tu-mour retention of 5FU appears to depend on thesize of the ∆pH, increases in pHi or decreases inpHe can also increase 5FU concentrations in cellsin solid tumours. It is hoped that strategies suchas these can be exploited to concentrate cytotoxicagents selectively in tumours. In addition, chroniclowering of tumour cell pHi, either by inhibition ofthe Na1/H1 exchanger with amiloride23, or by in-hibition of the Na1-dependent HCO3

2/Cl2 ex-changer with amiloride-analogues, is cytotoxic toisolated tumour cells and inhibits tumour growth24.

Future research approachesPossible approaches to answering some of thequestions raised in this article include: (1) deter-mining the in vivo rates of glycolysis in tumour typesof differing differentiation status, this could beachieved by using 13C MRS techniques; (2) investi-gating the location and mechanism of H1 move-ments between intra- and extracellular compart-ments – as the pH of the arterial supply and thevenous drainage can, in principle, be measured di-rectly, appropriate modelling could allow the pres-ent generation of (MR) pHe probes to be used to investigate this; (3) investigating the role of hypoxia-related gene expression in determining the cancermetabolic phenotype , this information could be ob-tained from genetically-manipulated cells grown assolid tumours in vivo; (4) determining the control andregulation of the glycolytic pathway exerted by hy-poxia-related gene expression, this informationcould be provided by metabolic control analysis10.By understanding how tumour pH is controlled, weshould be able to exploit it to selectively concentratecytotoxic agents in tumour cells.

Acknowledgements. Our work is sponsored by theCancer Research Campaign (CRC), UK.

References1 Warburg, O. (1930) The Metabolism Of Tumours,

Arnold Constable, London2 Griffiths, J.R. et al. (1981) 31P-NMR investigation of

solid tumours in the living rat. Biosci. Rep. 1, 319–3253 Vaupel, P. et al. (1989) Blood flow, Oxygen and nu-

trient supply, the metabolic microenvironment of

Figure 3. Modulation of tumour pH to increase uptake of chemotherapeutic drugs. The figure indicates themodulation (decrease or increase) of pH necessary to increase the uptake of the named drugs, which areweak electrolytes21.

Tumour cell

Lower pHe

5FURB-6145CamptothecinChloramphenicol

Higher pHe

AdriamycinVinblastineMitoxanthrone

Higher pHi

5FU

Molecular Medicine Today

The outstanding questions

• Are the high rates of glycolysis in tumours determined by changes ingene expression?

• Does hypoxia-related gene expres-sion determine the tumour metabolicphenotype?

• Is the extracellular acidity of tu-mours an intrinsic feature of theirmetabolic phenotype?

• Does changing the set point of pHi orpHe cause extracellular acidity?

• Could hypoxia be a feed-forward ac-tivator of invasiveness/metastasis?

human tumours: a review. Cancer Res. 49,6449–6465

4 Gillies, R.J. et al. (1992) Role of intracellular pH inmammalian cell proliferation, Cell. Physiol.Biochem. 2, 159–179

5 Stubbs, M. (1998) in Tumour pH, Blood perfusionand Microenvironment of Human tumours:Implications for Clinical Radio-Oncology. DiagnosticImaging and Radiation Oncology (Molls, M. andVaupel, P. eds), Vol. 11, pp. 113–120, Springer-Verlag, Berlin

6 Gillies, R.J. et al. (1994) 31P-MRS measurements ofextracellular pH of tumours using 3-aminopropyl-phosphonate. Am. J. Physiol. 267, C 195–203

7 Frenzel, T. et al. (1994) Non-invasive in vivo meas-urements using a fluorinated pH probe and fluorine-19 magnetic resonance spectroscopy. Invest.Radiol. 29, S220–S222

8 Weber, G. (1968) Carbohydate metabolism in can-cer cells and the molecular correlation concept.Naturwissenschaften 55, 418–429

9 Davies, S.E. and Brindle, K.M. (1992) Effects ofoverexpression of phosphofructokinase on glycoly-sis in the yeast Saccharomyces cerevisiae.Biochemistry 31, 4729–4735

10 Fell, D. (1996) in Understanding the control ofmetabolism. Frontiers in Metabolism (No. 2) (Snell,K. ed.), Portland Press

11 Gleadle, J.M. and Ratcliffe, P.J. (1998) Hypoxia andthe regulation of gene expression. Mol. Med. Today4, 122–129

12 Semenza. G.L. et al. (1997) Structural and func-tional analysis of hypoxia-inducible factor 1. KidneyInt. 51, 553–555

13 Maxwell, P.H. et al., (1999) The tumour suppressorprotein VHL targets hypoxia-inducible factors foroxygen-dependent proteolysis. Nature 399,271–275

14 Stubbs, M. et al. (1999) Causes and consequencesof acidic pH in tumours; a magnetic resonance study.Adv. Enzyme Regul. 39, 13–30

15 Newell, K. et al. (1993) Studies with glycolysis-defi-cient cells suggest that production of lactic acid isnot the only cause of tumour acidity. Proc. Natl.Acad. Sci. U. S. A. 90, 1127–1131

16 Yamagata, M. et al. (1998) The contribution of lacticacid to acidification of tumours: studies of variantcells lacking lactate dehydrogenase. Br. J. Cancer77, 1726–1731

17 Folkman, J. (1996) Tumour angiogenesis and tissuefactor. Nat. Med. 2, 167–168

18 Gatenby, R.A. and Gawlinski, E.T. (1996) A reac-tion-diffusion model of cancer. Cancer Res. 56,5745–5753

19 Ivanov, S.V. et al. (1998) Down-regulation of trans-membrane carbonic anhydrases in renal cell carci-noma cell lines by wild-type von Hippel–Lindautransgenes. Proc. Natl. Acad. Sci. 95, 12596–12601

20 Stubbs, M. et al. (1994) Metabolic consequences ofa reversed pH gradient in rat tumours. Cancer Res.54, 4011–4016

21 Gerweck, L.E. (1998) Tumour pH: implications for

treatment and novel drug design. Semin. Radiat.Oncol. 8, 176–182

22 Ojugo, A.S.E. et al. (1998) Influence of pH on theuptake of 5-Fluorouracil into Lettre ascites tumourcells. Br. J. Cancer 77, 873–879

23 Yamagata, M. and Tannock, I.F. (1996) The chronicadministration of drugs that inhibit the regulation ofintracellular pH: in vitro and anti-tumour effects.Br. J. Cancer 73, 1328–1334

24 Vukovic, V. and Tannock, I.F. (1997) Influence of lowpH on cytotoxicity of paclitaxel, mitoxanthrone andtopotecan. Br. J. Cancer, 75, 1167–1172

Marion Stubbs DPhil*Deputy Director

Paul M.J. McSheehy PhDSenior Research Fellow

John R. Griffiths MB, BS, DPhilDirector

C. Lindsay Bashford DPhil.Reader in Biochemistry

CRC Biomedical MR Research Group,Department of Biochemistry, St. George’s Hospital

Medical School, London, UK SW17 0RE.Tel: 144 181 725 5852

Fax: 144 181 725 2992e-mail: mstubbs@sghms.ac.uk

19

OpinionMOLECULAR MEDICINE TODAY, JANUARY 2000 (VOL. 6)

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