The Use of Rodent Tumors in Experimental Cancer Therapy Conclusions and Recommendations from an International Workshop1'2

[CANCER RESEARCH 45, 6541-6545, December 1985]

Meeting Report

This workshop was convened to address the question of how of a specific tumor cannot be predicted with any certainty. Virus- best to use animal models of solid tumors in cancer therapy induced rodent tumors almost always express common virus- research. The discussion among the 58 participants focused on coded antigens and are usually strongly immunogenic, but hosts the following topics: appropriate solid tumor models; xenografts neonatally infected with virus may be immunologically tolerant to of human tumors; assay systems such as local tumor control, virus-coded antigens. Chemically induced rodent tumors tend to clonogenic assays following tumor excision, and tumor regrowth express individually distinct antigens. Depending partially upon delay; and applications of such models in chemotherapy, radio the carcinogen and the target organ, the degree of immunoge therapy, and combined modalities studies. nicity is variable, but a large proportion of chemically induced A major goal of the meeting was to produce a set of guiding tumors are immunogenic. Spontaneous rodent tumors are usu principles for experiments on animal tumors. This report is largely ally nonimmunogenic, although a minority may be weakly to a statement of those guiding principles, with suggestions and moderately immunogenic (1, 2). comments concerning investigations using animal models in Because no tumor can be expected to be nonimmunogenic if cancer therapy research.3 The authors believe that this discus it is placed in an allogeneic environment, tumors should as a sion of "tricks of the trade" will be useful to research workers general rule only be transplanted syngeneically. Also it should be who are unfamiliar with the various procedures, but it should be noted that passage of cells through serum-containing medium recognized that they are based on current information and that may alter immunogenicity because of adsorbed serum proteins it is axiomatic in science that the current knowledge base is which cannot easily be washed off (3, 4). Immunogenicity may continuously being modified and reinterpreted. induce a rejection response and may thus invalidate the results of in vivo experiments, particularly those involving tumor re Tumor/Host Systems sponse to cytotoxic treatments. Therefore evaluation of the immunogenicity of the tumor-host system being used is always Model Systems in Cancer Research. An animal tumor model necessary, notwithstanding the etiology of the tumor, and should should be selected according to the question being asked. There be undertaken at appropriate intervals. Tumor immunogenicity is no single good model for cancer therapy research, and no may be ascertained using challenge-protection tests, after suit single system can be expected to be applicable to all problems. able preimmunization, as described elsewhere.23 Spontaneous tumors, early syngeneic passages of spontaneous Host Animals. To maintain syngeneic conditions between tumors, xenografted human tumors, or established transplant- tumor and host, as far as it is possible to do so, the animals able tumor lines can each be appropriate for investigating specific used as hosts must be acceptably homozygous and homoge questions. Because no single tumor system is a perfect model, neous at all times. It is desirable that every inbred subline be institutions and/or laboratories should endeavor to have available established by at least 40 generations of brother-sister inbreed more than a single tumor system for investigations of questions ing (5) and then be perpetuated by full sibling matings. Genetic related to cancer therapy. purity should be tested by second set skin grafts. Sublines of Tumor Immunogenicity. Evidence of immunogenicity of hu inbred animals can be expected to drift genetically and hence man tumors is derived from clinical anecdotes or from in vitro will vary with respect to their compatibility with each other and experiments and must be regarded in most instances as of with established tumor cell lines. Publications should give details unproven relevance to tumor rejection in vivo. In most human of sublines according to accepted convention (6-8). Genetic drift tumors, there is no unequivocal evidence that host immunity in both animals and tumors may be limited by freezing both plays a part in response to therapy. This supports the choice of embryos and tumor cells, respectively. nonimmunogenic models for experimental therapy studies (1). An exception to the general rule that tumor-host systems In laboratory animals, although the immunogenicity of tumor should be syngeneic is the use of human tumors transplanted types tends to be correlated with etiology, the immunogenicity xenogeneically into laboratory animals. Xenografts are attractive as model systems because of their clinical origins. There is a

Received 4/4/85; revised 8/15/85; accepted 9/10/85. modest amount of data suggesting that xenografts to some 1This international workshop on "The Use of Rodent Tumors in Experimental extent maintain the therapeutic sensitivity of the source human Cancer Therapy" was held on October 21-24, 1984, in Schloss Reisensburg, tumor (9), despite the fact that changes in tumor cell kinetics Federal Republic of Germany. It was supported by USPHS Grant CA 38523, and in parenchyma-stroma relationships occur during xenograft- awarded by the National Cancer Institute, Department of Health and Human Services, and by grants from the Deutsche Forschungsgemeinschaft, Bad Godes- ing. Because xenografts can be grown only in immunodeficient berg, Federal Republic of Germany, and the Sir Samuel Scott of Yews Trust, animals, such systems are prone to artifacts arising from residual London, United Kingdom. 2The complete proceedings of the workshop will be published separately in immunity or from immunological responsiveness which returns book form by Pergamon Press in 1986. to the host animals. Very careful and controlled experimentation 3 Several of the basic procedures and related information have been summarized is required if these problems are to be avoided. in a set of appendices to this report. They will be distributed by R. F. Kallman upon request. Xenografts may be used profitably to study inherent properties

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Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1985 American Association for Cancer Research. MEETING REPORT of human tumor cells, such as drug metabolism, cellular sensitiv for investigating treatments that cannot kill sufficient numbers of ity to drugs and radiation, and intracellular repair. It must be cells to achieve cure. This is particularly a problem in investiga tions of cytotoxic drugs. Radiation "top up" (14) is one useful remembered that the vasculature and connective tissue of a human tumor xenograft in a mouse are murine in origin; therefore means of obtaining tumor control curves when the tumor is not some properties of xenografts that depend strongly on the controlled by drug alone, but interaction between the drug and stroma may deviate considerably from those of the source tumor radiation can generate serious problems in the analysis of such in the patient. An example of this could be the degree of hypoxia. experiments. Thus if this method is to be used, interaction of Tumors. To maintain the stability of an established tumor line, this kind should be carefully evaluated. samples should be preserved in the frozen state, e.g., in liquid Because of the long time (normally 120-180 days) that is nitrogen. To avoid drift in tumor characteristics during serial required to assess whether or not a tumor has been controlled, I.e., "cured," this assay method is very suitable for assessing transplantation, tumors should be renewed from the frozen stock at appropriate intervals; i.e., tumors should not be used for more effects of extended or fractionated treatment schedules. than about 20 serial passages in syngeneic hosts. Procedures Tumor Growth Delay Assay. The main advantage of the for freezing and thawing tumors and tumor cells are given in Ref. tumor growth delay assay (15) is that it is suitable for use with 10, and a suitable method whereby live in vivo and in vitro almost any experimental tumor provided that its size can be passage are alternated with frozen storage has been described measured. It can be used to test the effectiveness of a wide (11). range of doses, although it is usually not sensitive enough to Al tumor systems should be characterized before being used detect small effects, e.g., when less than about 50% of cells are for extensive studies, both to assist interpretation of data and to killed. Because the effect on growth occurs over such a wide facilitate identification of drift. Characterization of any tumor dose range, there is usually little need for doing extensive pilot model should include: (a) growth curve in vivo, and possibly in studies; this assay facilitates the examination of dose-dependent vitro, if applicable; (b) sensitivity to at least one reference agent, dose modification, e.g., as seen in relative biological effective e.g., radiation or drug; (c) plating efficiency, in vivo cloning ness experiments. Growth delay is more economical than local efficiency, or TDso,4 whichever is applicable; (d) degree of im- control in that assays usually can be done with fewer animals munogenicity; (e) morphology. In addition, cell kinetic parameters and in much less time. Also it can often be used with tumors and karyotype may be useful. It is desirable to check some or all that metastasize and that cannot be assayed by the local control of these parameters whenever a tumor is reestablished from method. frozen stock, because of the possibility that only a subpopulation Growth delay results from more than simply the killing of of cells may have survived preferentially the freezing and thawing clonogenic tumor cells. For this reason, it is usually not possible procedure. to derive accurate surviving fractions from growth delay dose- response curves. Because the end point is time dependent, Assay Procedures growth delay is difficult to interpret if the treatment is given over an extended period (16). In such studies, it is appropriate to The three major assay procedures that have been most widely assess growth delay from the time the last fractional dose is applied to examine treatment effects on solid tumors are dis delivered. Local control is a more appropriate assay for such cussed in this section: tumor control, tumor growth delay, and experiments. the measurement of cell survival following tumor excision.23 The results of growth delay assays are prone to distortion if Other assays, such as the tumor latency assay or the percentage there is an immunological reaction, especially during the regrowth of increase in life span assay, are not discussed because it is phase. If tumors are found to be controlled (i.e., to stop growing thought that only in special cases should they be used for solid permanently) in low dose groups, this suggests the possibility of tumor; for most experiments, one of the aforementioned three immunological complications, and the suitability of the tumor- procedures is preferable. The choice of assay system that is host system should be carefully reassessed. The results of appropriate depends upon the question being asked. growth delay (at high doses) and local control experiments are Local Tumor Control. This method is generally regarded as usually in good agreement if immunogenic tumors are not used; the experimental assay that is most directly relevant to the therefore either assay method is useful for the comparison of treatment of human cancers. It is believed to depend on the treatments. eradication of all clonogenic cells in the tumor and thus should Cellular Survival Assays following Tumor Excision. These be directly linked to cell survival (12). Essentially it is irrelevant assays have the advantage that they can measure survival whether tumor cells are killed directly as by X-ray treatment, directly. They are applicable over a wide dose range and can be e.g., or indirectly via the stroma as thought to occur in hyper- used to test treatments that are lethal to the host, such as whole- thermia. This assay can be applied to a wide range of tumors body irradiation or high drug doses. They can assess lesser including spontaneous experimental tumors or early generation amounts of damage than is possible with the in situ assay transplants, although it is not suitable for tumors with a high methods (local tumor control and tumor growth delay), and propensity to metastasize. Because the assay is severely com potentially they can achieve greater accuracy and resolution of promised by tumor immunogenicity (13), it is not suitable for use differences in the efficacy of treatments that are being compared. with xenografts. It can be applied only over a relatively narrow Because a cell suspension must be prepared, however, excision (and high) range of doses, which makes it generally unsuitable assays are not suitable for all tumors and can be subject to artifact. If an assay is performed with a cell suspension that is 4 The abbreviation used is: TDM, the number of cells that produce tumors in not representative of the tumor, the results will be referable only 50% of subjects or sites. to the subpopulation recovered and tested. Preparing a tumor

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cell suspension seems in many respects an art rather than a components of every tumor. These normal cells can vary in type science, and there is no single method that is always best or and number both prior to and after treatment and can influence applicable. Ideally the suspension method should be optimized the quantitative assessment of tumor cell clonogenicity, either for each tumor system individually, and the yield of viable clon- by a dilution effect or because they may themselves be able to ogenic tumor cells should be as high as attainable. The possibility form colonies in vitro (23). Further discussion of this issue is of interaction between the disaggregation procedure and the available separately.3 treatment agent should be considered. One approach is to determine dose-survival curves for a given treatment agent, Experimental Variables That Can Affect Assay Procedures using more than one disaggregation procedure. or the Interpretation of Results The reproductive integrity of the tumor cells in a suspension can be assessed either in vivo or in vitro. Methods for the former Several variables have been shown to influence assay results include the end point dilution assay (17,18) and the lung colony quantitatively and can thus produce artifacts in tumor experi (19) or spleen colony (for lymphomas, see Ref. 20) assays. For ments. These include animal health and husbandry, tumor site the latter, many tumor cells will form colonies in semisolid media and size, and treatment conditions. (agar or methylcellulose) and some special cell lines that have Animal Health and Husbandry. The health, housing, and been adapted to alternating in vivo-in vitro growth will form husbandry of animals used as tumor hosts and the bacterial-viral colonies on plastic or glass surfaces. These three types of assay status of both hosts and tumors are all important in influencing generally give similar survival values when compared head to tumor growth, tumor response, and host animal response to head using the same cell suspension, but each has its advan treatment. Contamination can be minimized by following sterile tages and disadvantages (21). End point dilution (TD60)assays precautions when handling tumor preparations and by using are suitable potentially for every tumor that can be made into a gnotobiotic animals. Poor health of host animals may result in suspension, while the assays based on colony counting require excessive mortality after treatment and, especially for the growth substantial work to establish whether they are suitable and/or delay assay, animal health should be carefully monitored. It is reliable for each tumor to be tested. However, TDso assays are also important that systemic side effects of treatment, e.g., more expensive, they require more time and effort in the cell weight loss, be recognized since they may affect growth rates handling phase, and they take longer for the results to be and otherwise compromise the results of any assay method. obtained than colony-type assays. In vitro colony assays are Site of Tumor Implantation and Tumor Size. For experiments usually quicker and simpler to perform than most in vivo meth testing localized tumor treatment, e.g., irradiation, the site of ods. Tumors to be tested by in vitro assays in liquid media tumor implantation should be chosen so that treatment can be (colonies on glass or plastic surfaces) should be maintained on given without excessive damage to adjacent normal structures. a strict alternating in vivo-in vitro growth schedule. (This is usually a minor problem if an excision assay is being Although in vitro assays generally provide better intraexperi- used.) Site selection is also important because the stroma of a ment statistics than in vivo assays because more colonies are tumor will differ in different sites. Tumors growing in different counted, variation between experiments is always larger. In other sites differ in blood flow, in growth rate, and in metastatic words, although perhaps they are capable of greater precision, potential. Tumors in the extremities, e.g., foot or tail, are at a in vitro assays are not necessarily more accurate. This fact lower temperature than at other sites. The latter is particularly illustrates why before drawing conclusions excision assay pro important when chemotherapeutic drugs are tested because cedures should be repeated a number of times for each treat drug uptake and metabolism are both temperature dependent. ment, using independent groups of tumors. A similar stricture Similarly, wide variations in rate of blood flow, fraction of hypoxic applies to all the various assay procedures used to assess tumor cells, and growth fraction occur over the size range that is often response to treatment. studied, between 5 and 15 mm average diameter. Thus it is An outstanding difference between the assays performed in important that the size of tumors at treatment be strictly stand situ and assays done with cells suspended from excised tumors ardized. is that, in the latter case, the tumor cells are deprived of any Treatment Conditions: Stress, Anesthesia, or Hypothermia. host-mediated or tumor microenvironmental factors that might If a localized treatment is to be given, then the investigator faces have an important influence on cellular responses to treatment. a dilemma. Both anesthesia and the stress that is always caused The importance of this can be addressed only by comparing by restraint can introduce significant serious artifacts which are results obtained using excision assays with those obtained using usually associated with changes in blood flow. Thus the supply in situ assays with the same tumor (22). Removal from the host of oxygen and nutrients may be sharply reduced and, especially may be an advantage if the tumor-host system is in any way in small animals, reductions in temperature may also occur. immunogenic, e.g., as in all xenografts. Hence, removing xeno- Although this cannot always be avoided, it should be controlled geneic tumor cells from the host animal in which they were by minimizing stress and/or using anesthetic conditions that treated in order to determine the effects of treatment by an in have the least effect on blood flow and physiological temperature vitro colony assay may effectively preclude interpretational prob regulation. lems that are associated with immunological rejection. There are significant problems associated with applying exci Influence of Treatment Modality on Experimental Design sion assay methods to tumors given fractionated or extended treatments, and it is difficult to interpret the results generated by Experiments with chemotherapeutic agents or other drugs such experiments. Not the least of the difficulties arises from the differ in important ways from experiments with radiation, and normal cells, i.e., stroma, blood-borne cells, etc., that are major this requires different approaches to experimental design and to

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Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1985 American Association for Cancer Research. MEETING REPORT the interpretation of results. Some of the important factors are gate any schedule or combined treatment. discussed below. As in studies with any single modality, potential therapeutic Exposure Time. For radiation, the dose rate throughout the effectiveness of different regimens should be compared relative tumor is reasonably uniform and the dose is usually delivered to the same level of normal tissue toxicity. It is most useful if the over a short time. For drugs, the concentration at the target site normal tissue damage approximates that seen in clinical practice. is variable and there may be poor or uneven distribution in the If combining two agents gives the same degree of injury to a tumor. The duration of exposure is usually longer than for critical normal tissue but an enhanced antitumor effect, this should result in a "therapeutic gain." That condition may or may radiation and depends upon the pharmacokinetics of the agent under study, which varies with the animal species (and can be not reflect supraadditivity (24) in the action of the two agents. very different between mice and humans). This can be a partic Isobologram analysis (25) provides a useful framework for the ular problem when an excision assay method is used to investi identification of supraadditivity, but it does not reveal underlying gate a drug effect. The influence of time between drug adminis mechanisms. In order to be able to make predictions about the tration and excision must be examined in order to avoid or clinical effectiveness of any regimen, knowledge of the respon minimize artifacts arising from incomplete cell killing, the car sible mechanism is necessary. ryover of drug into the suspension medium, the interaction of Models for Adjuvant Therapy. Experiments on the optimiza drug with agents used in the preparation of a cell suspension, or tion of adjuvant therapy for occult micrometastases may be insufficient time for repair of potentially lethal damage. Most of performed using either spontaneous or artificial mÃ©tastases.The these difficulties can be precluded by the use of in situ assay former are provided by several tumors known to metastasize to methods. Even though grossly measurable nonimmunogenic specific sites. The latter may be produced by the i.v. injection of tumors are rarely cured by drug treatment, tumor control curves a tumor cell suspension. In any case, the response of a metas can be obtained using radiation "top up" (see "Assay Proce tasis may be very different in the different phases of its growth, dures"). Alternatively a regrowth delay assay is convenient and especially in the early phases when it lacks its own vasculature. can provide valuable information. Because nonlethal effects of Moreover, the size distribution, the number of tumor cells per drugs are common, however, the relationship between regrowth metastasis, and the total number of tumor cells are of crucial delay and cell survival will often be complex so that extrapolation importance for response to chemotherapy. The vascularization, from regrowth delay to cell survival usually is not justified. growth pattern, and kinetics of the metastatic lesions should be Cell Cycle Effects and Scheduling. Chemotherapeutic drug established for any models that are to be used in adjuvant effects are more cell cycle stage and proliferation dependent therapy studies. than are radiation effects. Because the effect of a second or Ethical Principles Especially Relevant to Cancer Therapy subsequent treatment (drug or radiation dose) may be critically Research dependent on the cell cycle distribution of the cells surviving the preceding treatment(s), knowledge of the cell cycle kinetics of Investigators are obliged to have the utmost concern for the surviving clonogenic cells is of paramount importance. Study of welfare of the experimental animals they use. In addition to the proliferation kinetics of the whole cell population will provide conforming to governmental and institutional requirements, un useful information only during the late recovery phase when necessary distress should be avoided. For example, whenever most damaged cells have been lost from the population. The possible an end point tumor size should be established and emergence of resistant cell populations also poses a problem in animals should be sacrificed promptly upon attaining that size. It the response of tumors to drugs, particularly when they are given is seldom necessary, within the context of the experimental in multidose regimens. procedures discussed in this report, to allow a tumor to exceed Drug Resistance. Because drug-resistant variants of trans approximately 10% of the body weight of the animal. planted tumors can be expected to occur as a function of drug Robert F. Kallman5 dose and duration of exposure, model systems used in experi J. Martin Brown mental chemotherapy must be evaluated periodically. Insofar as Department of Radiology the phenomenon of intrinsic drug resistance is the object of Stanford University School of Medicine investigation, that condition should be distinguished from envi Stanford, California 94305 ronmentally induced resistance. (Drug-resistant cell populations can be obtained by expanding resistant clones, usually in vitro; Juliana Denekamp these should be used to retest cell sensitivity.) Gray Laboratory Combined Modality Experiments. In experiments investigat Northwood, United Kingdom ing combinations of modalities, those technical problems that are associated primarily with irradiation (e.g., the tumor bed Richard P. Hill effect) and those that are associated uniquely with chemotherapy Ontario Cancer Institute (e.g., residual drug effects) may interact in complex and occa Toronto, Ontario, Canada sionally unpredictable ways. This will introduce difficulties in interpreting experimental results, especially if regrowth delay or Johan Kummermehr excision assays are used. Klaus-RÃ¼digerTrott The well-known variability among different types of tumors as University of Munich well as the heterogeneity within tumors may give rise to still Munich, Federal Republic of Germany greater variability in the effects of combined modalities. For this reason, it is essential to use several different tumors to investi 5To whom requests for reprints should be addressed.

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Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1985 American Association for Cancer Research. The Use of Rodent Tumors in Experimental Cancer Therapy: Conclusions and Recommendations from an International Workshop

Robert F. Kallman, J. Martin Brown, Juliana Denekamp, et al.

Cancer Res 1985;45:6541-6545.

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