augmentation of cytotoxicity of chemotherapy by human Â ... · augmentation of cytotoxicity of...

[CANCER RESEARCH 46, 4916-4920, October 1986]

Augmentation of Cytotoxicity of Chemotherapy by Human Â«-Interferonsin HumanNon-Small Cell Lung Cancer XenograftsJames Carmichael,1 Ronald J. Fergusson, C. Roland Wolf,2 Frances R. Balkwill,3 and John F. Smyth4

Imperial Cancer Research Fund, Medical Oncology Unit, Department of Clinical Oncology, Western General Hospital, Edinburgh EH4 2XV, Scotland, united Kingdom

ABSTRACT

Three human non-small lung cancer xenograft lines were used to studythe activity of combinations of cytotoxic drugs with human a-interferons(IFNs). Statistically significant potentiation of cÂ»-platinum(CDDP) andcyclophosphamide (CY) given weekly in a low dose was seen when humanlymphoblastoid interferon (IFN-anl) (2 x 10* /u/mouse/day) was admin

istered simultaneously. The median tumor doubling times for CDDP inthe three tumors (35, 22, and 29 days) increased to 52, 51, and 41 dayswhen IFN-anl was added. A similar though less marked effect was seenwith CY (median doubling time increased from 21.5, 19.5, and 27 daysto 32, 27, and 35 days with the addition of IFN-anl). IFN-anl alone atthis dosage was shown to have some cytotoxic activity. Similar potentiation of CDDP and ifosfamide was seen in two tumors when humanrecombinant a-2 interferon was added at a lower dose (2 x III' /Â¿/mouse/

day). Median doubling times for CDDP increased from 17 and 14 daysto 27 and 18.5 days with the addition of human recombinant a-2 interferon, whereas for ifosfamide they increased from 11.5 and 14 days to 15and 16 days. Human recombinant a-2 interferon in this dose had no effectas a single agent.

INTRODUCTION

The outlook for the majority of patients with disseminatednon-small cell lung cancer remains very poor. Recently, improved response rates have been achieved with platinum-containing regimens (1), although the duration of these remissionshas been limited and the considerable toxicity associated withthese combinations precludes their widespread use (2). Muchinterest has been shown recently in the use of human IFNs5

which have been shown to have modest antitumor activity in anumber of human tumors (3-7); however, single agent activityhas not been seen in either small cell lung cancer (8) or non-small cell lung cancer (9-10).

More recently attention has been focused on the use of IFNsin combination with cytotoxic drugs. Several workers (11-13)have shown potentiation of chemotherapeutic agents by IFNsin vitro and these positive interactions have been confirmed invarious animal models. In 1973 Chirigos and Pearson (14)showed that murine IFN increased the cure rate of the LSTRAmurine leukemia by BCNU from 25 to 72% despite beingineffective as a single agent. Gresser et al. (15) demonstratedan additive antitumor effect between murine IFN and CY inthe spontaneous lymphoma of AKR mice and a similar effecthas been shown with CY and murine IFN in the C1300 mouse

Received 1/4/86; revised 6/3/86; accepted 6/16/86.The costs of publication of this article were defrayed in part by the payment

of page charges. This article must therefore be hereby marked advertisement inaccordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1Present address: National Cancer Institute, National Cancer Institute-NavyMedical Oncology Branch, Naval Hospital, Bethesda, MD 20892.

2Present address: Imperial Cancer Research Fund, Laboratory of Molecular

Pharmacology and Drug Metabolism, University of Edinburgh, Department ofBiochemistry, Hugh Robson Building, George Square, Edinburgh, Scotland,United Kingdom.

3 Imperial Cancer Research Fund, Lincoln's Inn Fields, London, England,

United Kingdom.4To whom requests for reprints should be addressed.5The abbreviations used are: IFN, interferon; IFN-anl, human lymphoblastoid

interferon; r!FN-a2b, human recombinant a-2 interferon; CY, cyclophosphamide;CDDP, cis-platinum; IFOS, ifosfamide; SGD, specific growth delay; /",,, doubling

time; MTD, maximum tolerated dose.

neuroblastoma (16). Balkwill and Moodie (17) showed markedsynergy between human lymphoblastoid IFN and low doses ofCY and Adriamycin against a human breast tumor xenograftgrowing in nude mice.

The purpose of this study was to ascertain whether humanIFN-as could potentiate the activity of cytotoxic chemotherapyin the treatment of human non-small cell lung cancers usingbiopsies xenografted into immune deprived mice.

MATERIALS AND METHODS

Animals. CBA mice, immune deprived by means of thymectomy, 1-,3-D-arabinofuranosylcytosine and X irradiation (18) were used in thisstudy. Mice were thymectomized at 3 weeks of age and then were given735 cGy whole body \-irradiation 3 weeks later, having received apriming dose of l-/3-D-arabinofuranosylcytosine, 200 mg/kg i.p. 48 hbefore. Implantation of the tumor was carried out the day followingirradiation, and the mice were treated with terramycin and neomycinin acidified drinking water for 14 days. The mice were housed in aseparate room in the animal unit but specific pathogen-free conditionswere not required.

Tumors. Three non-small cell lung cancer xenograft lines were tested.The tumors were derived originally from specimens removed at surgeryfrom previously untreated patients. Their growth characteristics andmorphology have been described elsewhere (19). The xenografts wereall studied during the 5th-11th passages. The 3 xenograft lines usedwere: (a) NX 002, moderately differentiated squamous carcinoma; (b)CX 117, poorly differentiated adenocarcinoma; and (c) CX 143, aden-osquamous carcinoma.

All xenograft tumors had maintained the histological features oftheir original tumor, and the karyotypes were confirmed to be human.A minimum of 6 tumors were entered in each group with the exceptionof one group for which there were only 4 assessable tumors (CX 117,cÃ's-platinumalone). Tumors were measured twice weekly using calipers

and the tumor volume was estimated using the formula for an ellipsoid

Volume â€¢x/W2

where D is the longest diameter and d is the smallest diameter. Onlytumors with an estimated minimal tumor volume of 0.3 cm3 were used

for drug testing.Interferons. Two human Â«-interfÃ©ronswere evaluated in these exper

iments. (IFN-anl) (Namalwa) was prepared as previously described (20)and was kindly provided by Wellcome Research Laboratories (Beck-enham, Kent, United Kingdom). It had a specific activity of 1-2 x 10*units/mg and was essentially pure; 2 x 10s units in 0.1 ml were injected

s.c. each day for 35 days at a site distant to the tumors. This dose isequivalent to approximately 20 x IO6 units/m2 daily in humans using

the calculations of Freireich et al. (21).rIFN-a2b (Schering Corporation, Bloomfield, NJ) with specific ac

tivity of 1.7 x 10* units/mg [>98% pure (2)] was injected in a dose of2 x IO4units/mouse/day for 35 days as above (equivalent to approximately 2x10* units/m2 in humans).

Cytotoxic Drugs. cw-Platinum (Bristol-Myers, Ltd., Slough, UnitedKingdom) was dissolved in sterile normal saline and administered at adosage of 1.4 mg/kg i.p. on days 0, 7, 14, 21, and 28. This dose wasequivalent to 20% of the maximum tolerated dose previously determined in these animals. Cyclophosphamide (Farmitalia Carlo Erba,Ltd., St. Albans, United Kingdom) and ifosfamide (Boehringer Ingel-heim, Bracknell, United Kingdom) were dissolved in sterile water for

4916

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IFN AND CHEMOTHERAPY COMBINATIONS IN LUNG XENOGRAFTS

injection and administered at a dosage of 40 and 60 mg/kg i.p.,respectively, following an identical schedule.

Study Design. Groups of tumors were randomly allocated to treatment with drug or IFN alone, drug and IFN in combination, or acontrol group. CDDP and CY were assessed with the high dose IFNregime in all three tumors. CDDP and IFOS were used with the lowdose IFN regimen in the NX002 and CXI 17 tumors.

Response to treatment was assessed by measurement of the mediantumor volume T,>after treatment and calculation of the SGD using theformula (23)

SGDTp (treated) - TD (control)

To (control)

The SGD represents the number of tumor doubling times delayed bytreatment and allows comparisons to be made between drugs in tumorsof different growth rates. Statistical differences between the mean TDsof treated and control groups were carried out using an unpairedStudent's i test.

In the model, survival is not influenced by tumor growth and cannottherefore be used as an end point. Experimental results are presentedup until the time of tumor doubling.

RESULTS

High Dose IFN-anl and Chemotherapy. The changes in median TO and SGD for the high dose IFN-anl/chemotherapycombinations are illustrated in Figs. 1 and 2.

NX002. Control tumors had a median TD of 16 days. IFNalone caused an increase in median TD to 21.5 days and anSGD of 0.34. The increase in mean TD was not statisticallysignificant. Median T0 with CDDP was 35 days (SGD =1.18),

(a) N>50

40

Â«30Â°

n10

n<OO2

Ibi C)

so40â€ž30

5 20

10

0<1_-17

(cl CX143

sor

'20

CONTROl IFN CODPCOOPâ€¢UN

Fig. 1. Effect of high dose IFN-anl (IFN) (2 x 10* units/mouse/day s.c. for35 days), CDDP (1.4 mg/kg i.p., weekly x 5), CY (40 mg/kg, Â¡.p.,weekly x 5),and high dose IFN-anl/CDDP and CY combinations on the median doublingtime of the 3 non-small cell lung cancer xenografts. Minimum of 6 tumors/group,except CDDP alone in CXI 17 (4 tumors).

NXOO22.0

1.0

00CONTROL

CX1 173.0

2.0

IFN CDDP CDDPâ€¢IFN

CYCLO CYCLO+IFN

1.0

0.0 LCONTROL IFN CDDP CDDP CYCLO CYCIO

If N Â«IFN

CX1432.0 r

1.0

0.0râ€”CONTROlIFN CDOP CDDPCYCID+

IFNCYCIO +IFN

Fig. 2. Effect of high dose IFN-anl (IFN) (2 x IO5 units/mouse/day s.c. for35 days), CDDP (1.4 mg/kg Â¡.p.,weekly x 5), CY (CYCLO) (40 mg/kg Â¡.p.,weekly x 5), and high dose IFN-anl/CDDP and CY combinations on the specificgrowth delay of the 3 non-small cell lung cancer xenografts. Minimum of 6tumors/group.

but the increase in mean TD compared with controls was notsignificant. When CDDP and IFN were given in combinationthe median TD was 52 days (SGD = 2.25) with the mean TDsignificantly longer than controls (P < 0.01) and than CPPDalone (P < 0.05). It is also noteworthy that in this combinedtherapy group 2 tumors remained static and one regressedcompletely. CY alone had an effect similar to IFN alone (median TO= 21.5 days; SGD = 0.34) and although its effectivenesswas increased when combined with IFN (median TD= 32 days;SGD = 1.0) the increase in mean TDwith either CY or CY incombination with IFN was not significantly different fromcontrols.

CXI 17. Control tumors had a median TD of 13 days. IFNalone caused a significant prolongation of mean TD (P < 0.05)with median TD= 23 days and SGD = 0.77. CDDP alone gavea similar median TDand SGD (22 days and 0.69) but the meanTO did not differ significantly from controls. When CDDP wascombined with IFN there was a marked effect (median TD= 51days; SGD = 2.92) with a significant increase in mean TDP <0.002 versus control and P < 0.02 versus CDDP alone. CYalone was less effective than IFN or CDDP alone (median TD= 19.5 days; SGD = 0.5) but when combined with IFN it wasmore effective (mean TD= 21 days; SGD = 1.07) with the meanTO differing significantly from the control group (P < 0.03). Pfor the combination versus cyclophosphamide alone was notsignificant (0.29).

CX143. Control tumors had a median TD of 16 days. IFN,CDDP, and CY alone all caused an increase in median TD(IFN23 days, SGD = 0.44; CDDP 29 days, SGD =; 0.81; CY 27days, SGD = 0.68) but as single agents their mean TD did notdiffer significantly from controls. The combination of CDDPand IFN gave a median TD of 41 days (SGD = 1.56) with astatistically significant increase in the mean TD (P < 0.04).Comparing the combination with CDDP alone the results werenot statistically significant (P = 0.34). CY and IFN in combination gave a greater effect than either as a single agent (medianTo = 35 days; SGD = 1.18); however, the mean T0 did not

4917




differ significantly from controls. In this tumor 5 xenograftsremained static (1 control, 2 CDDP, 1 CDDP and IFN, 1 CYand IFN) and 4 regressed (2 CDDP and IFN, 2 CY and IFN).

(a) N;

3020I

1011<CO2

CONTROL IFN CDDP CDDP IFOSIFOS+IFN+ IFN

(W CX1 17

30 r

S 300

Ã¯

1. 200

100

CONTROL

IFOS*IFN

10 20Days

30 40

Fig. 6. Inhibitory effects of low dose rIFN-a2b (Â«W)/IFOS combination onthe growth of the squamous lung cancer xenograft NX002. rIFN-o2b, 2 x IO4units/mouse/day s.c.; IFOS, 60 mg/kg i.p., weekly. Minimum of 6 tumors/group.Results are up until the time of tumor doubling.

20

0LIONTROLIFÂ« CDDP CDDP IFOSIFOS-IF

* IFN

Fig. 3. Effect of low dose rIFN-a2b (IFN) (2 x IO4 units/mouse/day s.c. for35 days), CDDP (1.4 mg/kg i.p., weekly x 5), IFOS (60 mg/kg i.p., weekly x 5),and low dose rIFN-Â«2b/CDDP and IFOS combinations on the median doublingtime of 2 non-small cell lung cancer xenografts NX002 and CXI 17. Minimumof 6 tumors/group.

NXOO2

2.0

1.0

0.0CONTROL IFN CODP CDDP

â€¢IFNIFOS IFOS'IFN

CX1 17

2.0

1.0

0.0CONTROL IFN CDDP CDOP

If N

IFOS IFOS+IFN

Fig. 4. Effect of low dose rIFN-a2b (IFN) (2 x 10* units/mouse/day s.c. for35 days), CDDP (1.4 mg/kg i.p., weekly x 5), IFOS (60 mg/kg i.p., weekly x 5),and low dose rIFN-Â«2b/CDDP and IFOS combinations on the specific growthdelay of 2 non-small cell lung cancer xenografts NX002 and CXI 17. Minimumof 6 tumors/group.

300

m

IDO

CONTROL

CDOP- IFN

0 10 20 30 Â«Days

Fig. 5. Inhibitory effects of low dose rIFN-Â«2b(IFN)/CDDP combination onthe growth of the squamous lung cancer xenograft NX002. rIFN-a2b, 2x10*

units/mouse/day s.c.; CDDP, 1.4 mg/kg i.p., weekly. Minimum of 6 tumors/group. Results are up until the time of tumor doubling.

Low Dose IFN-t*2b and Chemotherapy. The effect of low doserIFN-a2b either alone or in combination with CDDP and IFOSon the median TDand SGD in NX002 and CXI 17 is illustratedin Figs. 3 and 4.

NX002. The effect of IFN, CDDP, and IFOS on tumorgrowth rates is shown in Figs. 5 and 6. The median 7"Dfor

control tumors was 9 days. The increase in growth rate fromthe high dose IFN experiments was thought to be related torepeated passage. Low dose IFN had no effect in this tumor asa single agent (median 7"D= 10 days; SGD = 0.11). Treatment

with CDDP alone caused a significant increase in mean TDcompared with controls (P< 0.04; median TD= 17 days; SGD= 0.88). The addition of low dose IFN to CDDP increased thepotency further (median TD= 27 days; SGD = 2.0) with a moresignificant prolongation of mean TD (P < 0.005). IFOS hadlittle activity alone (median TD = 11.5 days; SGD = 0.28) butwhen IFN was added an increased effect was seen (median TD= 15 days; SGD = 0.67) with the mean TD significantly prolonged compared with controls (P < 0.04) and compared withIFOS alone (P < 0.05). Three tumors (1 CDDP, 2 CDDP plusIFN) regressed in this experiment.

CX 117. Median TD for control tumors was 12.5 days. IFNalone had no effect at this dosage. CDDP and IFOS as singleagents caused small increases in median TDto 14 days (SGD =0.12); CDDP and IFN in combination gave a significant prolongation of mean TDcompared with controls (P< 0.02; medianTo = 18.5 days; SGD = 0.48). The addition of IFN to IFOSdid not significantly improve its potency (median TD= 16 days;SGD = 0.28).

DISCUSSION

In 3 human non-small cell lung cancer xenografts we havedemonstrated potentiation of chemotherapy with 3 drugs bythe addition of 2 different human IFNs. This effect was mostmarked when IFN-anl was given in high dosage with CDDP inthe adenocarcinoma CXI 17. For both the CXI 17 tumor andthe squamous cell NX002 the addition of interferon to CDDPwas significantly better than the use of CDDP alone. This doseof IFN-anl (2 x IO5units/mouse/day) which is equivalent to a

dose unlikely to be tolerated by man, had a significant effectwhen given alone and it was for this reason that the experimentswere repeated with a lower dose of rIFN-a2b (2 x IO4 units/

mouse/day) in an attempt to mirror more closely the clinicalsituation. At this lower dose rIFN-a2b had no effect alone butwas able to augment the activity of CDDP in CXI 17 and ofCDDP and IFOS in NX002.

The high dose IFN-anl experiments were performed with

4918




Namalwa Â¡nterferon which contains several a-interferon subtypes. Encouraged by these initial results we subsequently performed the low dose experiments with r!FN-a2b which containsonly the a-2 subtype. Since the antitumor profile of differentIFN preparations may differ, and since the IFN-anl experiments were performed with doses that would exceed humantolerance, we performed the low dose experiments with ther!FN-Â«2b preparation with which we have clinical experienceand which we would use in clinical trials with cytotoxic drugs.These experiments confirm previous reports of enhanced activity seen with combinations of chemotherapy and IFNs in certainmurine tumors (14-16) and in human breast cancer xenografts(17). To our knowledge this is the first report of this effect inhuman lung cancer.

Although we have demonstrated that the combination of IFNand chemotherapy is more effective than would be expectedfrom the potency of each as a single agent it is not possible toprove a synergistic relationship from these data; however, thefact that r!FN-Â«2b in low dose had no effect alone yet was ableto increase the activity of both CDDP and IFOS in combination(Figs. 5 and 6) is strong evidence of a positive or synergisticinteraction.

The xenograft system used for these experiments has beenvalidated by a close correlation between experimental resultsand the therapeutic activity of the same cytotoxic drugs in theoriginal tumors in humans (24, 25). These experiments validating our xenograft model pertain to drug sensitivity or resistancecomparisons rather than effects pertaining specifically to doseand schedule. In the experiments reported here we chose todivide the MTD into 5 aliquots in order to assess the responseover a relatively chronic exposure with IFN; but further studiesare required to define the optimal dose schedule for suchcombinations. Such studies are now in progress. Clearly theMTD of one schedule differs from the MTD of another. Inclinical practice CDDP in particular causes significant toxicityon its own (2) and in clinical trials great caution will have to beexercised to avoid potentiation of unacceptable toxicity resulting from CDDP-IFN combinations.

Despite the extensive clinical trials with IFN-a there is todate no clearly defined dose-response effect in man, and theoptimal schedule of administration remains to be determined(26). There is, however, widespread agreement that for tumorssuch as non-Hodgkin's lymphoma and hairy cell leukemia,

where IFN is active on its own, the duration of therapy is atleast as important as the dose administered. It was for thesereasons that we designed the experiments reported here toexplore the use of IFN and cytotoxic drugs scheduled repeatedlyover a period of weeks, rather than a single, maximally toleratedexposure.

Since the xenograft model depends on the immune deprivation of the mouse host, we are aware of the possible immuno-logical effects of IFN that might artificially appear to potentiatethe cytotoxicity of anticancer drugs in this system. It is knownthat murine IFN affects natural killer cell activity (27) anddepresses the activity of the hepatic cytochrome P-450 systemin the mouse (28). These effects have to be considered whenmurine IFN is tested in combination with cytotoxic drugs inexperimental murine cancers (14-16). Such effects are not seenwhen human IFN and anticancer agents are used to treat humantumors grown in immunodeficient mice (29, 30). This suggeststhat the positive interactions between IFN and chemotherapyin such a system is likely to be due to a direct action on thetumor itself rather than due to an influence on the host tissues.The precise mechanism of IFN potentiation of chemotherapy

is unclear although it may be related to changes in the tumorcell cycle (30).

In our experiments IFN potentiated CDDP to a much greaterextent than CY or IFOS. The reason for this is unclear butaccepting the clinical toxicity of CDDP it is important to assessthe potential augmentation of other cytotoxic drugs both by aand other IFNs in this model. Such studies are now in progress.

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16. Tozawa, M., KJdowaki, T., Tamaka, T., Sawada, T., Kusunoki, T., Oku, T.,and Kishida, T. Effects of interferon on Cl 300 mouse neuroblastoma. CancerTreat. Rep., 66: 1575-1577, 1982.

17. Balkwill, F. R., and Moodie, E. M. Positive interactions between humaninterferon and cyclophosphamide or Adriamycin in a human tumor modelsystem. Cancer Res., 44:904-908, 1984.

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19. Fergusson, R. J., Carmichael, J., and Smyth, J. F. Human tumour xenograftsgrowing in immunodeficient mice: a useful model for assessing chemotherapeutic agents in bronchial carcinoma. Thorax, 41: 376-380, 1986.

20. Fantes, K. H., Kurnian. C. J., Ball, G. D., and Finter, N. B. The productionpurification and properties of human lymphoblastoid interferon. In: TheBiochemical Characterisation of Lymphokines, pp. 343-351. New York:Academic Press, Inc., 1980.

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IFN AND CHEMOTHERAPYCOMBINATIONSIN LUNG XENOGRAFTS

F. Smyth(eds.),InterferonAlpha-2:Pre-clinicalandClinicalEvaluation,pp. 27. Djeu,J. V. Heinbaugh,J. A., Holden,H. T., andHeberman,R. B.Augmen-1-12. Boston:MartinusNijhoff,I98S. tation of mouse naturalkiller cell activity by interferonand interferon

23. Kopper,L.,andSteel,G. G. Thetherapeuticresponseof threehumantumor inducers.J. Immuni)!..122:175-181, 1979.lines maintainedin immunesuppressedmice.CancerRes., 35: 2704-2713, 28. Singh,G., Renton,K.W., andStebbing,N. HomogenousinterferonfromE.

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1986;46:4916-4920. Cancer Res James Carmichael, Ronald J. Fergusson, C. Roland Wolf, et al. -Interferons in Human Non-Small Cell Lung Cancer Xenografts

αAugmentation of Cytotoxicity of Chemotherapy by Human

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