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The culture of human tumour stem cells clinical prospects in cancer chemotherapy
78 has been obtained from work on isolated membrane particles. Yet, properties and tegulation of this system as a mediator effects of physiological of Ihe catecholamines, have to be studied in intact cells. Quite a number of observations indicate that bindii constants and cychtse activation characteristics defined in membrane particles cannot be strictly applied to calculate stoichiometric stimulus-effect rela tionships in living tissues. Some regulatory changes in the&eceptor/adenylate cyckse system, e.g. adaptive increase or decrease in receptor numbers, remain stable during homogenization and membrane pteparation. Only intact cell studies will help to decide wkther these changes are ako physiologically the most important ones.
and Leviwki.
2 Delis. B. Ii. and Wilwn.
277.
1. 8. (1980) 1. Riol.
Chem. 255,l043-Iou1
Hoycr.D.. Berthod.R. and Wapner. (IYIW) Naunw-Schmiedelwqs Arch. Phwmokul. 31 I. R f3 *I Rcdbell.M. (198U)Nnru4(Lonulon)ZRJ.17-22 3 Terasaki.W. L. andB&cr. 0. (197OJ. Biol.
: Engel, CL
H.
ChewI. 253.5418-5425 h
Ins& P. and Slmlman, L. M. (1978) Phamwcol.
fi4Or.
14,54%561
7 Kaumann. A. J.. Mclnemy. T. K., Gilmmu. D. P. and Blinks. 1. Il. (1980) Avh. I]
Phwmukd.
Nuunytn-Schmieddwrp
31 I, 219-234
Tcrepki. W. L.. Linden, 1. and Bmdrcr. 0. (1979) Pnx Nad Acod. Sri. U.S.A. 76. 64016405
9 Williams. Reaper
L.. T. and Lentowirz, Binding
Sfctdirs
in
R. 1. (1978) Adwwgir
RavenPress.New York IO Hornburger. V.. Lucas.M., Cancau,9.. Bamk. 1.. Pevit. 1. and Bocknen,1. (1980) J. Bid Phamuwlogy.
I Pockr. R. andSchmiu.H. (1979)N17hrre(tin. don) 277.5~..59; reply by Atlas. D.. Hanski. E.
A. (1979) Nufscrc (LonJonJ
59-60
Chem. 255 II
I9436-16444
Johnson.CI. L. Wolfe. B. B.. Harden.T. K..
The culture of human tuikur stem cells Clinical prospe6ts in cancer chemotherapy Guy Riou and Jean Berm-d It is now possible to culture human nunour C&Y m vitro and test rhe activ@ of antineopiastic drugs. This chemogram predicts rhe luck of eficacy of drugs in vivo with high accuracy.
Clinicians today have at their disposal some 30 chemical substances (not including hormones and theii derivatives) to Lght effriently against human cancers. To be activeinman.lheszdrugsrequiretobe used at concenwations close to toxic doses. Consequently the chemotherapist co, stantly faces tk activity-toxicity dilemma. On one hand, in order to eliminate malignant tumour cells. he must administer high doses of
the drug; yet on the other hand, a suff&nt number of normal cells must be preserved to allow healtby tissues. e.g. hematopoietic tissues, to regenerate. We know the great success of antibis tics in the f&d of antimkmbial treatment: those were due to UX exploitation of the nmjor biological differences between human cells and bacterial cells. leading to pi high tbcrapeutic index. The problem is quite different in cancer chemotherapy: fm. we know nothing of tbe biiogieal mechankms which explain how and why a
cell becomes malignant and. in addition, there are no fundamental biochemical differences between a normal cell and a cancerous ceil. Most anticancer drugs have a low therapeutic index and this is one failing of chemotkxapy. However, metabolic differences are perceptible: it would be interesting to take advantage of those differences, which would allow us, for instance, to base the drugs’ selective toxicity against malignant cells. In the past few years, in vitro culture in agar medium or human tumour cells has allowed chemothempy or radiotherapy prs
dictive trials to be carried ouPa. Salmon and his collaborators have developed a predictive ‘chemogram’ based on tbe xnsitivity or resistance of clonogenic cells to drugs’. ff rhe drug inhibits the tumour cells growth in virr0, it is likely to be a+fe in the patient; on the contrary, if it does not pvent the development of malignant cells in vitro. it must be dii fronl treat
ment. In the following, we alhall try firs1 to describe this attractive new technique, then to discuss its advantages in the short and long term.
Culture ofclonogenic celk fofhuman tm: drug testing In continuously renewing tissues, like bone mamlw for instance. nhere is a sub population of stem cells accounting for about 1% of the total cell pJpulatiolls. By ru&gy, and considering ttiat the cells in many tumours keep the imorphological characteristics of theii original tissue, the hypothesis has been proposed, thal tumours also include a s&population of stem cells. The stem cells of tumotal origin are defined as cells that give rise to a large family of descendants which a~ specific for the tumoum and have the ability to generate other stem celks. These cells generally account for a small fraction of the tumour cell population and tbeii growth properties am different from those of most of the other cells forming the tumour. 1 is those stem cells which are responsible for the forms tion of metastases and they ate able to regrow a tumour after subcurative treatment. The stem-cell concept in tumours is well documented in the excellent review of Steele. The development of k v&o culture techniques allowed the tumour cells to grow under attiticial conditions (semi solid agar medium) and to produce ~lones’~‘~~. Only a small proportion of turnour cells retain the ubility to produce clones. Thete m grounds for believing that the cells which ate clonogenic under test conditions may be the same cells that are stem cells in vivo. In the experhnental conditions of this assay. a colony or cellular clone is obtained from a single cancercell. Only the hunout%
malignant stem cells form a cellular clone. Taking advantage of the imtmrtant teaching of these new studies, Salmon er d ‘.I’pro posed that this technique be used to predict the activity of anticancer drugs in patient. In practice, the starting material is a fresh turnout obtained aher -urgical excision; malignant cells am finely dilacerated so as to separate cells fmm one another wit~ut endangering their viabihty. Someof the iso. lated cells are incorporated right away in a soft agamse (0.3%) medium which is layered in a ‘pea: dish on a solid agarose tO.5~) sublayer. These cells will serve as a ‘controf . Theothersareallowedto incubate for a fixed time period with the drug. before it is included in the culture medium as described previously. After 1040 days, aLcoming to the tested car tyge. each tumour cell will multiply and form acolony of IO@-200cells (Figs 1 and 2); the colonies which have developed in each culture medium are then counted. If the drug is active, it wilt kill cells, which will no longer form a colony. ff it is inactive, the same number of colonies as in the control test will be obtained. Up to the present, interesting results have been obtained concerning several types of tumour eluding ovarian turnours, myelomas and meIanomase. The cortclations between the activities of drugs administered in the patient in viva and incubated with the ceilsin v&o am shown in Table I. Out of the 148 cotrelations described. the authors demonstrate that when malignant cells am sensitive in vitro, tumoursalsoaresensitivein viva in 6236of the cases. A relatively high rate of false positives, probably due to the fuct that the drug benefits by easier access to culture cells compared with patients’ tumour cells. However when malignant cells ate resistant in vitro, tumouts also are resistant in vivo in %9h oC the cases. aping to these results, this test seems to be exttemely useful in predicting the inefticucy of some drugs: these will have to be omitted horn the therapeutic regimen and a great deal of drug-induced ~idi~ will thus be a,,oided. Van Hoff et al. Iareportcomparable results concerning Ihe prediction of ineffiacy for certain drugs in vivo and in vitro. This tehiiue. though it seems to be a simple one at fust sight, is quite diffkndt
several IWs. These flight ceils do not cuhurc in rive with equal facility. Some turnouts gmw with difficulty an.: *nur clnning efficiency rb verv low. 0.0, to O.Os”iaand e\en less in uvnc cases. So. *hat can we infer from this: that some ttimours have d small number of stem cells, or else that the stem cells of these tumours grow with mnch difficulty? Some tumour cells can multiply only in very complex media, thr colitis of which is very hard to control. Great efforts must be made to improve the growing conditions of cermitt tumour cell types, especially in the field of nutrient media and gmwth factors. However decisive progress will be achieved only when we have a better knowledge of the mechanisms regulating the biological functions of these cells. Besides.
to carry out; it often gives a low success index and it is sometimes hard to interpret. ~W~~~~
A number of malignant tumours from various origins (ovary, kidney, breast. melanoma, colon, etc.) were cultured in
TUMOUR I
mechanical
dissociation
individual tumcu~al cells
lhour
37°C
Soft Agar
I
.:/,. -., .:i ., : .,, : a :...
“,,$.‘.;-‘,.; . . .
-. . \_;
. : j...
-:‘:I)
.‘I
.
“_’‘_
,...,
..
c
:;y:
,
‘.,
:,.:
:::
.. ._
‘,1”
,_i
.‘!C‘
,_ -.>
‘.
cells cultured in vitro in the ptosence of the various drugs conespoMfS to nbwn ]@-%a of the clinical C X I pmdttct, The in vitro way has B maximum sensitivity limit of 2 log units, as a consequence of a low plating efficiency. However, to detect a clinical response, deaths of ~rno~ cells corm6 ~~ingtoad~~a~of3~~i~mu~~ obtained. The drug concentrations used in clinics will therefore be IO times as high as the concentrations usedin vitro.
Fig.2. Phmc~gmph of ceUfd4rclonesdevelopingon so# 4g4mse. obt4ined fmnr 4 bm4.u a&-&‘?m4.
we must make sum that the ceik which give rise to clones are indeed tumour cells with the characteristics of the original tumour. In some casts a specific marker f3r a type of Nmour is &termined to control a clone’s cells. For instance vanillylmandelic acid is found is the culture medium of neurohlas. tomas which generate this metabolite. As far as the expcrimemal realization is concerned, this ‘clonogenic’ trial inchtdcs a difftult phase. i.e. the dilaccration of tumoral tissues into isolated cells, and a long and tedious phase. i.e. the optical microscop? counting of colonies in the culmrc medium.
Drug caacenb-irtimt to be used in lhe
ift
vitro biul What drug co~en~on should be used in t&o to correspond with &at existing in tbe cells inside the lumour after administra. tion in the patient? The data available to the experimenter am the pharmacokinetic parameters of the drug in man. For a given mute of lotion, the clinical concenuatiotime product C x t may he con. Sidered as a characteristic of the drug: it is the quantity of drug available after injection in the body. According to Sabnon~s erperimcnts. the sensitivity area of clonogenic
Cancer chemotherapy tumains. above all. an empirical science. The drugs which patients are prescribed have been selected on the basis of t~sults obtained b-am previous clinical trials. How should correlations be drawn between in vitro experimental results and clinical results? The in vitro activky of the different drugs used in the therapeutic regimen am tested. Several cases may arise. The drugs do not kill the cells in vitro anr! they aw clinically inactive too In that event, an easy and accurate correlation between these results appears. The correlation is quite aseasy and accurate if the drug is active in virro andin viva. However objective clinical impmvement as d&ted by clinicians often takes a IO@ time to assess, a& its weption sometimes requires subtlety. On the con. tw, if the drug is activein vitro and inao tive in vivo. or active in Tvo and inactive k vifru. socalled ‘false-positive’ or ‘fak+negative’
resuh.5are obtain&
These
wOtts are no good.
as they may mislead the clinician and make him lose precious time. An improvement in the described tech. niques should a!low a tiuction in the frequency of ‘false-positives’. A~plicationprospeas As mentioned above, many technical pmbtems remain before the human tumour stem cell assay brings a decisive element in chamotharapeutic prescription. For example, the testtlts reported hem have beerr determined using drugs singly, not in corn__ &&on
w iS a&
in cl&&
pwaie,
stem cells. Yet the most interesting pros, pect which this new method offers is its high potential for selecting new anticancer drugs. It will allow onone hand the Shorten ing of the fmt phase clinical trials, and on the other hand the testing of new drugs on a highly dive&f& sampling of human tumours. which is very impottant: a number of drugs found to be inactive in certain turnout-s have been excluded fmm therapy. Yet they might have proved active if tried in other types of tumottrs. In conclusion, we must be optimistic about the futum. le still have, as regards technical realization, considerable work to achieve, but we firmly Nieve that the culture of c~o~ge~c colts of human tumours will, in the near future, provide improW+ ment in cancer chemotherapy, and will aid the selection of new drugs. Readlrtg iilrt
I
Puck.T. T, end Marrus,P. 1.W56V. fkp. Med. 103.624-666 2 Bruce.W. R.. Meeker. 8. E. aml Vuteiiote.F. A. (1966)J. Nad CancerIns,. 37.233-245 3 Carrtcnay,V.D.,Setby.P.J.,Smith,t.E.,Mills. J. and Peckhem.M. J. (1978fBr. J. Gzncer, 38, 77-w 4 Hamburger. A. W. end Salmon. S. E. (1977)
Sriefw. 197.46 I-463 5 Pike.B. L. and Robinsan. W. A. t197O;J. Cell. Physiol. 76.77-84 6 Sral, G. G. fi977) in Growfk
Kkfks
of
Tumounc&X4.cr.G.. ed.). pp.217-267 7 Park. C. H.. Berg>aSel, D. E. and McCullwh. E. A. (1971)J. &‘a:orf C8nrwfnnt. 466.4II-I?2 8 Pa&ii. Z. P., Sbwm, H. K., Rusturn, Y I M.. Creawm,P. J.. Ncnvak, N. J., Kamkix&&C., Takka,H. OndMiaelnan, A. tI9iJO)cPnm Res. 40.4151-4158 9 Salmon, S. E.. Albens, D. S., Durie. 8. G. M.. Meyskem, F. L., Jones. S. E., Soehnten. 8.. Cben, H. S. G. andMoon,T. (1980)in Recwt Re&.s in oincpr Research &&if& 0. and Muggia. F, M.. eds;). Vol. 74 PP. 300-305. StningefVet@. Berlin 10 Van Hoff. D. D., Harris. 0. I., Johnson.G. and Gtaubi8er.D. ( 1980) in Hwwf Turnon Coon&g fsetmon. S. E.. ext.), PP. f 13-124. Alen Liss
co. NewY&L Guy Rfimre&~gdh& Ph.D. in Biochemiu~of die FarUlrpdesS&m-es in Pati in /Q@. He is 4 Pm@OF4~B~h~~ iR the Faculty~fhfedkke 4nd Pimmmcy of the U&miiy of Amiens rind Direcu~of the Clinical arrdM&cul4r Pharnulc31.
However. the formation of colonies of tumour cells in semi-solid culture medium 0g.vDepurrmear of the Inuihu Gwrow Rowy 01 has many potential applications in funda- u;,,ejGJ mental biological studies such as character- JetmRen4rdrece;wdhir Ph.I). iri &hwf&~fr? rif i=tio~ of factors billing cell gmwth f/l&! Unfit Q~~~~~Sin 1978. Heir Asskr4mbf and of biochemical properties of turnout- chewme /kp4nmenr.
and Leviwki.
2 Delis. B. Ii. and Wilwn.
277.
1. 8. (1980) 1. Riol.
Chem. 255,l043-Iou1
Hoycr.D.. Berthod.R. and Wapner. (IYIW) Naunw-Schmiedelwqs Arch. Phwmokul. 31 I. R f3 *I Rcdbell.M. (198U)Nnru4(Lonulon)ZRJ.17-22 3 Terasaki.W. L. andB&cr. 0. (197OJ. Biol.
: Engel, CL
H.
ChewI. 253.5418-5425 h
Ins& P. and Slmlman, L. M. (1978) Phamwcol.
fi4Or.
14,54%561
7 Kaumann. A. J.. Mclnemy. T. K., Gilmmu. D. P. and Blinks. 1. Il. (1980) Avh. I]
Phwmukd.
Nuunytn-Schmieddwrp
31 I, 219-234
Tcrepki. W. L.. Linden, 1. and Bmdrcr. 0. (1979) Pnx Nad Acod. Sri. U.S.A. 76. 64016405
9 Williams. Reaper
L.. T. and Lentowirz, Binding
Sfctdirs
in
R. 1. (1978) Adwwgir
RavenPress.New York IO Hornburger. V.. Lucas.M., Cancau,9.. Bamk. 1.. Pevit. 1. and Bocknen,1. (1980) J. Bid Phamuwlogy.
I Pockr. R. andSchmiu.H. (1979)N17hrre(tin. don) 277.5~..59; reply by Atlas. D.. Hanski. E.
A. (1979) Nufscrc (LonJonJ
59-60
Chem. 255 II
I9436-16444
Johnson.CI. L. Wolfe. B. B.. Harden.T. K..
The culture of human tuikur stem cells Clinical prospe6ts in cancer chemotherapy Guy Riou and Jean Berm-d It is now possible to culture human nunour C&Y m vitro and test rhe activ@ of antineopiastic drugs. This chemogram predicts rhe luck of eficacy of drugs in vivo with high accuracy.
Clinicians today have at their disposal some 30 chemical substances (not including hormones and theii derivatives) to Lght effriently against human cancers. To be activeinman.lheszdrugsrequiretobe used at concenwations close to toxic doses. Consequently the chemotherapist co, stantly faces tk activity-toxicity dilemma. On one hand, in order to eliminate malignant tumour cells. he must administer high doses of
the drug; yet on the other hand, a suff&nt number of normal cells must be preserved to allow healtby tissues. e.g. hematopoietic tissues, to regenerate. We know the great success of antibis tics in the f&d of antimkmbial treatment: those were due to UX exploitation of the nmjor biological differences between human cells and bacterial cells. leading to pi high tbcrapeutic index. The problem is quite different in cancer chemotherapy: fm. we know nothing of tbe biiogieal mechankms which explain how and why a
cell becomes malignant and. in addition, there are no fundamental biochemical differences between a normal cell and a cancerous ceil. Most anticancer drugs have a low therapeutic index and this is one failing of chemotkxapy. However, metabolic differences are perceptible: it would be interesting to take advantage of those differences, which would allow us, for instance, to base the drugs’ selective toxicity against malignant cells. In the past few years, in vitro culture in agar medium or human tumour cells has allowed chemothempy or radiotherapy prs
dictive trials to be carried ouPa. Salmon and his collaborators have developed a predictive ‘chemogram’ based on tbe xnsitivity or resistance of clonogenic cells to drugs’. ff rhe drug inhibits the tumour cells growth in virr0, it is likely to be a+fe in the patient; on the contrary, if it does not pvent the development of malignant cells in vitro. it must be dii fronl treat
ment. In the following, we alhall try firs1 to describe this attractive new technique, then to discuss its advantages in the short and long term.
Culture ofclonogenic celk fofhuman tm: drug testing In continuously renewing tissues, like bone mamlw for instance. nhere is a sub population of stem cells accounting for about 1% of the total cell pJpulatiolls. By ru&gy, and considering ttiat the cells in many tumours keep the imorphological characteristics of theii original tissue, the hypothesis has been proposed, thal tumours also include a s&population of stem cells. The stem cells of tumotal origin are defined as cells that give rise to a large family of descendants which a~ specific for the tumoum and have the ability to generate other stem celks. These cells generally account for a small fraction of the tumour cell population and tbeii growth properties am different from those of most of the other cells forming the tumour. 1 is those stem cells which are responsible for the forms tion of metastases and they ate able to regrow a tumour after subcurative treatment. The stem-cell concept in tumours is well documented in the excellent review of Steele. The development of k v&o culture techniques allowed the tumour cells to grow under attiticial conditions (semi solid agar medium) and to produce ~lones’~‘~~. Only a small proportion of turnour cells retain the ubility to produce clones. Thete m grounds for believing that the cells which ate clonogenic under test conditions may be the same cells that are stem cells in vivo. In the experhnental conditions of this assay. a colony or cellular clone is obtained from a single cancercell. Only the hunout%
malignant stem cells form a cellular clone. Taking advantage of the imtmrtant teaching of these new studies, Salmon er d ‘.I’pro posed that this technique be used to predict the activity of anticancer drugs in patient. In practice, the starting material is a fresh turnout obtained aher -urgical excision; malignant cells am finely dilacerated so as to separate cells fmm one another wit~ut endangering their viabihty. Someof the iso. lated cells are incorporated right away in a soft agamse (0.3%) medium which is layered in a ‘pea: dish on a solid agarose tO.5~) sublayer. These cells will serve as a ‘controf . Theothersareallowedto incubate for a fixed time period with the drug. before it is included in the culture medium as described previously. After 1040 days, aLcoming to the tested car tyge. each tumour cell will multiply and form acolony of IO@-200cells (Figs 1 and 2); the colonies which have developed in each culture medium are then counted. If the drug is active, it wilt kill cells, which will no longer form a colony. ff it is inactive, the same number of colonies as in the control test will be obtained. Up to the present, interesting results have been obtained concerning several types of tumour eluding ovarian turnours, myelomas and meIanomase. The cortclations between the activities of drugs administered in the patient in viva and incubated with the ceilsin v&o am shown in Table I. Out of the 148 cotrelations described. the authors demonstrate that when malignant cells am sensitive in vitro, tumoursalsoaresensitivein viva in 6236of the cases. A relatively high rate of false positives, probably due to the fuct that the drug benefits by easier access to culture cells compared with patients’ tumour cells. However when malignant cells ate resistant in vitro, tumouts also are resistant in vivo in %9h oC the cases. aping to these results, this test seems to be exttemely useful in predicting the inefticucy of some drugs: these will have to be omitted horn the therapeutic regimen and a great deal of drug-induced ~idi~ will thus be a,,oided. Van Hoff et al. Iareportcomparable results concerning Ihe prediction of ineffiacy for certain drugs in vivo and in vitro. This tehiiue. though it seems to be a simple one at fust sight, is quite diffkndt
several IWs. These flight ceils do not cuhurc in rive with equal facility. Some turnouts gmw with difficulty an.: *nur clnning efficiency rb verv low. 0.0, to O.Os”iaand e\en less in uvnc cases. So. *hat can we infer from this: that some ttimours have d small number of stem cells, or else that the stem cells of these tumours grow with mnch difficulty? Some tumour cells can multiply only in very complex media, thr colitis of which is very hard to control. Great efforts must be made to improve the growing conditions of cermitt tumour cell types, especially in the field of nutrient media and gmwth factors. However decisive progress will be achieved only when we have a better knowledge of the mechanisms regulating the biological functions of these cells. Besides.
to carry out; it often gives a low success index and it is sometimes hard to interpret. ~W~~~~
A number of malignant tumours from various origins (ovary, kidney, breast. melanoma, colon, etc.) were cultured in
TUMOUR I
mechanical
dissociation
individual tumcu~al cells
lhour
37°C
Soft Agar
I
.:/,. -., .:i ., : .,, : a :...
“,,$.‘.;-‘,.; . . .
-. . \_;
. : j...
-:‘:I)
.‘I
.
“_’‘_
,...,
..
c
:;y:
,
‘.,
:,.:
:::
.. ._
‘,1”
,_i
.‘!C‘
,_ -.>
‘.
cells cultured in vitro in the ptosence of the various drugs conespoMfS to nbwn ]@-%a of the clinical C X I pmdttct, The in vitro way has B maximum sensitivity limit of 2 log units, as a consequence of a low plating efficiency. However, to detect a clinical response, deaths of ~rno~ cells corm6 ~~ingtoad~~a~of3~~i~mu~~ obtained. The drug concentrations used in clinics will therefore be IO times as high as the concentrations usedin vitro.
Fig.2. Phmc~gmph of ceUfd4rclonesdevelopingon so# 4g4mse. obt4ined fmnr 4 bm4.u a&-&‘?m4.
we must make sum that the ceik which give rise to clones are indeed tumour cells with the characteristics of the original tumour. In some casts a specific marker f3r a type of Nmour is &termined to control a clone’s cells. For instance vanillylmandelic acid is found is the culture medium of neurohlas. tomas which generate this metabolite. As far as the expcrimemal realization is concerned, this ‘clonogenic’ trial inchtdcs a difftult phase. i.e. the dilaccration of tumoral tissues into isolated cells, and a long and tedious phase. i.e. the optical microscop? counting of colonies in the culmrc medium.
Drug caacenb-irtimt to be used in lhe
ift
vitro biul What drug co~en~on should be used in t&o to correspond with &at existing in tbe cells inside the lumour after administra. tion in the patient? The data available to the experimenter am the pharmacokinetic parameters of the drug in man. For a given mute of lotion, the clinical concenuatiotime product C x t may he con. Sidered as a characteristic of the drug: it is the quantity of drug available after injection in the body. According to Sabnon~s erperimcnts. the sensitivity area of clonogenic
Cancer chemotherapy tumains. above all. an empirical science. The drugs which patients are prescribed have been selected on the basis of t~sults obtained b-am previous clinical trials. How should correlations be drawn between in vitro experimental results and clinical results? The in vitro activky of the different drugs used in the therapeutic regimen am tested. Several cases may arise. The drugs do not kill the cells in vitro anr! they aw clinically inactive too In that event, an easy and accurate correlation between these results appears. The correlation is quite aseasy and accurate if the drug is active in virro andin viva. However objective clinical impmvement as d&ted by clinicians often takes a IO@ time to assess, a& its weption sometimes requires subtlety. On the con. tw, if the drug is activein vitro and inao tive in vivo. or active in Tvo and inactive k vifru. socalled ‘false-positive’ or ‘fak+negative’
resuh.5are obtain&
These
wOtts are no good.
as they may mislead the clinician and make him lose precious time. An improvement in the described tech. niques should a!low a tiuction in the frequency of ‘false-positives’. A~plicationprospeas As mentioned above, many technical pmbtems remain before the human tumour stem cell assay brings a decisive element in chamotharapeutic prescription. For example, the testtlts reported hem have beerr determined using drugs singly, not in corn__ &&on
w iS a&
in cl&&
pwaie,
stem cells. Yet the most interesting pros, pect which this new method offers is its high potential for selecting new anticancer drugs. It will allow onone hand the Shorten ing of the fmt phase clinical trials, and on the other hand the testing of new drugs on a highly dive&f& sampling of human tumours. which is very impottant: a number of drugs found to be inactive in certain turnout-s have been excluded fmm therapy. Yet they might have proved active if tried in other types of tumottrs. In conclusion, we must be optimistic about the futum. le still have, as regards technical realization, considerable work to achieve, but we firmly Nieve that the culture of c~o~ge~c colts of human tumours will, in the near future, provide improW+ ment in cancer chemotherapy, and will aid the selection of new drugs. Readlrtg iilrt
I
Puck.T. T, end Marrus,P. 1.W56V. fkp. Med. 103.624-666 2 Bruce.W. R.. Meeker. 8. E. aml Vuteiiote.F. A. (1966)J. Nad CancerIns,. 37.233-245 3 Carrtcnay,V.D.,Setby.P.J.,Smith,t.E.,Mills. J. and Peckhem.M. J. (1978fBr. J. Gzncer, 38, 77-w 4 Hamburger. A. W. end Salmon. S. E. (1977)
Sriefw. 197.46 I-463 5 Pike.B. L. and Robinsan. W. A. t197O;J. Cell. Physiol. 76.77-84 6 Sral, G. G. fi977) in Growfk
Kkfks
of
Tumounc&X4.cr.G.. ed.). pp.217-267 7 Park. C. H.. Berg>aSel, D. E. and McCullwh. E. A. (1971)J. &‘a:orf C8nrwfnnt. 466.4II-I?2 8 Pa&ii. Z. P., Sbwm, H. K., Rusturn, Y I M.. Creawm,P. J.. Ncnvak, N. J., Kamkix&&C., Takka,H. OndMiaelnan, A. tI9iJO)cPnm Res. 40.4151-4158 9 Salmon, S. E.. Albens, D. S., Durie. 8. G. M.. Meyskem, F. L., Jones. S. E., Soehnten. 8.. Cben, H. S. G. andMoon,T. (1980)in Recwt Re&.s in oincpr Research &&if& 0. and Muggia. F, M.. eds;). Vol. 74 PP. 300-305. StningefVet@. Berlin 10 Van Hoff. D. D., Harris. 0. I., Johnson.G. and Gtaubi8er.D. ( 1980) in Hwwf Turnon Coon&g fsetmon. S. E.. ext.), PP. f 13-124. Alen Liss
co. NewY&L Guy Rfimre&~gdh& Ph.D. in Biochemiu~of die FarUlrpdesS&m-es in Pati in /Q@. He is 4 Pm@OF4~B~h~~ iR the Faculty~fhfedkke 4nd Pimmmcy of the U&miiy of Amiens rind Direcu~of the Clinical arrdM&cul4r Pharnulc31.
However. the formation of colonies of tumour cells in semi-solid culture medium 0g.vDepurrmear of the Inuihu Gwrow Rowy 01 has many potential applications in funda- u;,,ejGJ mental biological studies such as character- JetmRen4rdrece;wdhir Ph.I). iri &hwf&~fr? rif i=tio~ of factors billing cell gmwth f/l&! Unfit Q~~~~~Sin 1978. Heir Asskr4mbf and of biochemical properties of turnout- chewme /kp4nmenr.