Purpose: We looked at the value of three preclinical cancer models, the in vitro human cell line, the human xenograft, and the murine allograft, to examine whether they are reliable in predicting clinical utility. Experimental Design: Thirty-one cytotoxic cancer drugs were selected. Literature was searched for drug activity in Phase II trials, human xenograft, and mouse allografts in breast, non-small cell lung, ovary, and colon cancers. Data from the National Cancer Institute Human Tumor Cell Line Screen were used to calculate drug in vitro preclinical activity for each cancer type. Phase II activity versus preclinical activity scatter plot and correlation analysis was conducted for each model, by tumor type (disease-oriented approach), using one tumor type as a predictor of overall activity in the other three tumor types combined (compound-oriented approach) and for all four tumor types together. Results: The in vitro cell line model was predictive for non-small cell lung cancer under the disease-oriented approach, for breast and ovarian cancers under the compound-oriented approach, and for all four tumor types together. The mouse allograft model was not predictive. The human xenograft model was not predictive for breast or colon cancers, but was predictive for non-small cell lung and ovarian cancers when panels of xenografts were used. Conclusions: These results suggest that under the right framework and when panels are used, the in vitro cell line and human xenograft models may be useful in predicting the Phase II clinical trial performance of cancer drugs. Murine allograft models, as used in this analysis, appear of limited utility.

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Clinical Predictive Value of the in Vitro Cell Line, Human Xenograft, and Mouse Allograft Preclinical Cancer Models

Purpose: To determine demographic data and define prognostic factors for long-term outcome in patients presenting with high-grade osteosarcoma of bone with clinically detectable metastases at initial presentation. Patients and Methods: Of 1,765 patients with newly diagnosed, previously untreated high-grade osteosarcomas of bone registered in the neoadjuvant Cooperative Osteosarcoma Study Group studies before 1999, 202 patients (11.4%) had proven metastases at diagnosis and therefore were enrolled onto an analysis of demographic-, tumor-, and treatment-related variables, response, and survival. The intended therapeutic strategy included pre- and postoperative multiagent chemotherapy as well as aggressive surgery of all resectable lesions. Results: With a median follow-up of 1.9 years (5.5 years for survivors), 60 patients were alive, 37 of whom were in continuously complete surgical remission. Actuarial overall survival rates at 5 and 10 (same value for 15) years were 29% (SE = 3%) and 24% (SE = 4%), respe...

Primary Metastatic Osteosarcoma: Presentation and Outcome of Patients Treated on Neoadjuvant Cooperative Osteosarcoma Study Group Protocols

Currently used rodent tumor models, including transgenic tumor models, or subcutaneously-growing human tumors in immunodeficient mice, do not sufficiently represent clinical cancer, especially with regard to metastasis and drug sensitivity. In order to obtain clinically accurate models, we have developed the technique of surgical orthotopic implantation (SOI) to transplant histologically-intact fragments of human cancer, including tumors taken directly from the patient, to the corresponding organ of immunodeficient rodents. It has been demonstrated in 70 publications describing 10 tumor types that SOI allows the growth and metastatic potential of the transplanted tumors to be expressed and reflects clinical cancer. Unique clinically-accurate and relevant SOI models of human cancer for antitumor and antimetastatic drug discovery include: spontaneous SOI bone metastatic models of prostate cancer, breast cancer and lung cancer; spontaneous SOI liver and lymph node ultra-metastatic model of colon cancer, metastatic models of pancreatic, stomach, ovarian, bladder and kidney cancer. Comparison of the SOI models with transgenic mouse models of cancer indicate that the SOI models have more features of clinical metastatic cancer. Cancer cell lines have been stably transfected with the jellyfish Aequorea victoria green fluorescent protein (GFP) in order to track metastases in fresh tissue at ultra-high resolution and externally image metastases in the SOI models. Effective drugs can be discovered and evaluated in the SOI models utilizing human tumor cell lines and patient tumors. These unique SOI models have been used for innovative drug discovery and mechanism studies and serve as a bridge linking pre-clinical and clinical research and drug development.

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Orthotopic metastatic mouse models for anticancer drug discovery and evaluation: a bridge to the clinic.

Polymer conjugates may possess anticancer activity through a variety of mechanisms. The macro-molecules themselves may have anticancer activities, or, more typically, inert biocompatible polymers serve as carriers for low molecular weight anticancer agents. Polymer conjugates may also be targeted to increase the concentration of conjugate in the vicinity of a specific subset of cells. This article reviews the recent literature that pertains to polymer conjugates with anticancer activity. The types of polymers chosen as drug carriers and the biodistribution of polymers in the body are discussed. Also, the synthesis, biological properties, and the means used to evaluate the anticancer activities of polymer conjugates are detailed.

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Papers

Experimental screening procedures and clinical predictability value.