Limitations of the human tumour xenograft system in individual patient drug sensitivity testing

Bailey, M J; Jones, Adrian; Shorthouse, A. J.; Raghaven, D.; Selby, P.; Gibbs, John L.; Peckham, M. J.

doi:10.1038/bjc.1984.242

Cited by 18 publications

(9 citation statements)

References 12 publications

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“…The direct comparison of drug response between a xenograft and a donor patient is difficult because of the relatively low take rates, the long delay between establishing and subsequently testing xenografts, and the small proportion of donor patients who receive only chemotherapy [5]. Another factor that makes such a comparison difficult is that usually in drug testing only one drug is evaluated at a time, whereas these same drugs are rarely used as single agents in the clinic.…”

Section: Direct Comparison Studies Between Xenograft and Donor Patientmentioning

confidence: 99%

Human tumor xenografts as model for drug testing

et al. 1988

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This paper reviews the history of xenografts, the endpoints commonly used to evaluate response and chemotherapeutic results obtained with serially maintained human tumor xenografts from different laboratories, and discusses the potential clinical relevance of the heterotransplant model for cancer chemotherapy. Specifically, an attempt is made to correlate the published xenograft data with the clinical data. Drug testing with different types of xenotransplanted tumors has shown that the response of xenografts obtained in immune-deficient animals is comparable to that in clinical practice. In addition, xenografts of a particular tumor type are able to identify agents of known clinical activity against that disease.

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Section: Direct Comparison Studies Between Xenograft and Donor Patientmentioning

confidence: 99%

Human tumor xenografts as model for drug testing

et al. 1988

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“…With regard to in vivo models, chemosensitivity testing of human tumors implanted in nude mice usually involves 30-50 weeks or more to obtain data and is, therefore, of limited use for most cancer patients (22). Another in vivo approach has been to implant human tumor tissue in the subrenal capsule of mice to determine drug sensitivity.…”

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confidence: 99%

In vivo-like drug responses of human tumors growing in three-dimensional gel-supported primary culture.

Vescio¹,

Redfern²,

Nelson³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

116

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An in vitro test of cell sensitivity to drugs that indicates in vivo response is an important need in cancer therapy and cancer drug development. Toward this end, we previously developed a collagen gel-supported culture system for growth of human tumors. This three-dimensional culture system is general and grows tumors at high frequency directly from surgery or biopsy that maintain important in vivo properties in vitro, including tissue architecture. We report here that with autoradiographic techniques measuring cellular DNA synthesis the drug responses of individual cells within the tissue structure of in vitro-grown tumors can be determined. Twenty tumor classes, including all the major ones, have been measured in toto at >50% frequency. Quantitative and qualitative results show increasing cell kill with rising cytotoxic drug concentration, differential drug sensitivities of multiple cell types within individual cultured tumors, differential sensitivities of a series of tumors of the same histopathological classification to a single drug, differential sensitivities of individual tumors to a series of drugs, and sensitivity patterns of various tumor types similar to the sensitivities found in vivo.Therefore, the results indicate that potentially important therapeutic data can be obtained from tumor specimens growing in vitro for the individual cancer patient as well as for rational and relevant screening for new agents active against human solid tumors.A major clinical problem is that cancers that are classified as identical according to their histopathological characteristics are nonetheless highly individual in their drug sensitivities and there is currently no way to predict clinical outcome of chemotherapy for individual patients (1). A second major problem is that there is currently no relevant assay to screen for new human anticancer agents, especially for solid tumors (2). To overcome these problems, many attempts have been made to develop in vitro drug-sensitivity tests for individual cancer patients about to undergo chemotherapy and to screen for new anticancer agents. These attempts have suffered in one form or another from their inability to support growth of human tumors such that they reflect the in vivo situation. Plating of dissociated tumor cells in soft agar (3)(4)(5)(6)(7)(8)(9)(10)(11)(12) and monolayer cultures (13-15) does not in many instances allow the growth of tumor cells. Often, when tumor cells do grow under these conditions, other cell types present in the original tumor probably have not grown. It is critical that cell types present in the original tumor be present in the assay since it has been shown that interactions between cell types can alter their drug sensitivities (16). Multicellular spheroids that are three-dimensional have been used recently for drug sensitivity testing (17,18), but these also involve dissociation of cells from the tumor and reassociation into structures that do not resemble the original tissues. Short-term in vitro assays of drugs on noncultured n...

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“…In contrast, poor correlations have been found between such models and predictions about individual patients with respect to their cancer's natural history (12), metastatic pattern (13), and absolute responsiveness to radiation, cytotoxic drugs, and immunological manipulation (14).…”

Section: Translational Modelingmentioning

confidence: 99%

Bladder Cancer: Optimal Application of Preclinical Models to Suitable Translational Questions

Raghavan

2010

Sci. Transl. Med.

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Bladder cancer is a paradigm of solid tumor malignancy, and despite increased understanding of the molecular biology of this disease, cure rates have not changed greatly for 20 years. Further progress is being slowed by poor accrual of patients to structured clinical trials. The use of preclinical models, and in particular bladder cancer xenografts and cell lines, may allow more rational design of clinical trials, provided that the experimental questions posed are within the capability of the respective models. With the availability of targeted therapeutic drugs for treating bladder cancer, these models may be useful for the design of drug combination regimens and optimal sequencing of reagents.

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Limitations of the human tumour xenograft system in individual patient drug sensitivity testing

Cited by 18 publications

References 12 publications

Human tumor xenografts as model for drug testing

Human tumor xenografts as model for drug testing

In vivo-like drug responses of human tumors growing in three-dimensional gel-supported primary culture.

Bladder Cancer: Optimal Application of Preclinical Models to Suitable Translational Questions

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