Cancer

Standard Induction:

For standard xenograft models, female mice (5 to 6 weeks old) are injected subcutaneously with 0.1 mL of viable human tumor cells on the flank region. All tumor cells are tested for infections agents at University of Missouri at Columbia, RADIL lab, and certified clean prior to their use.

Trocar Injection Induction:

Several tumor models, such as the OVCAR-3 human ovarian tumor and the BT474 human mammary tumor, are difficult to consistently grow in vivo when using tissue culture cells. For these models, it is necessary to first generate a few established tumors in severe combined immunodeficient (SCID) mice, or nude mice, and then harvest tumors aseptically, divide into fragment pieces and re-implant those fragments into a cohort of nude mice. For such studies tumor cells obtained from the American Type Culture Collection (ATCC) or other repository are expanded in tissue culture and checked for any infectious agents at the University of Missouri prior to injecting in mice. Once tumors are established, the subcutaneous tumors are removed aseptically and divided in 4 mm3 pieces. These tumor fragments can be cryogenically preserved for future retrieval and use in future studies, or re-implanted immediately. Female mice (5 to 6 weeks old) are implanted subcutaneously with a tumor fragment 4 mm3 of viable tumor on the flank region, using 11 gauge trocar needles.

Disease Parameters:

In these models, tumor growth is monitored and test agent treatment is typically initiated once tumors reach a weight range of 100 to 400 mg.

Dosing Paradigms:

  • Begin dosing on study day 0 and continue for X doses until termination.
  • Route of administration: SC, PO, IP, IV

Clinical Assessment:

Mice are visually inspected daily and when visible tumors are evident, tumor size is measured with vernier calipers and tumor volume determined using the formula: Length x Width2/2. When tumor size equals 200 mg +/- 100 mg, the mice are assigned to treatment groups.1-6 End points used to assess drug efficacy include evaluations of tumor growth (comparing tumors in treated versus control mice), tumor cell kill (log10 cell kill), and tumor regression. Regressions are defined as partial if the tumor weight decreases to 50% or less of the tumor weight at the start of treatment without dropping below 63 mg (5 x 5 mm tumor). Both complete regressions (CRs) and tumor-free survivors are defined by instances in which the tumor burden falls below measurable limits (<63 mg).7

Notes:

These strains of immunocompromised mice vary with regard to the degree of residual immunity and are required to allow the growth of human tumors. Nude mice are the earliest strain of immunocompromised rodents that have been used for growing human tumors and are still the most common strain used. However, some more difficult to grow tumors have been shown to grow in Severe Combined Immunodeficient Mice strains (SCID) where they fail to grow in nude mice. This requires the use of several different strains of immunodeficient mice that have been shown to support the growth of a given tumor line depending on the specific tumor model used.

Optional Endpoint

  • PK/PD blood collections
  • Cytokine/chemokine analysis via Luminex(R)
  • Other sandwich ELISAs
  • CBC/clinical chemistry analysis
  • Soft tissue collection
  • Histopathologic analysis
  • Immunohistochemistry analysis

References:

  1. World Cancer Report 2014, ed. B.W. Stewart and C.P. Wild, WHO press.
  2. The Nude Mouse in Oncology Research, ed. Epie Boven and Benjamin Winograd, CRC Press, 1991.
  3. Fogh,J., Fogh,J.M. and Orfeo, T., One hundred and twenty-seven cultured human tumor cell lines producing tumors in nude mice, J. Natl. Cancer Inst., 59, 221, 1977.
  4. Povelson, C. O. and Jacobsen, G. K., Chemotherapy of a human malignant melanoma transplanted in the nude mouse, Cancer Res., 35, 2790, 1975.
  5. Povlsen, C. O. and Rygaard, J., Heterotransplantation of human adenocarcinomas of the colon and rectum to the mouse mutant nude. A study of nine consecutive transplantations, Acta Path. Microbiol. Scand., 79, 159, 1971.
  6. Anticancer Drug Development Guide; Preclinical Screening, Clinical Trials, and Approval., Ed. Beverly A. Teicher., Humana Press, 1997.
  7. Teicher BA, editor. Anticancer drug development guide: preclinical screening, clinical trials, and approval. Totowa (NJ): Humana Press Inc; 1997. p. 75–125.

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