Severe Combined Immunodeficiency (Scid) Mouse Modeling of P-glycoprotein Chemosensitization in Multidrug-Resistant Human Myeloma Xenografts

William T. Bellamy, Abiodun Odeleye, Elizabeth Huizenga, William S. Dalton, Ronald S. Weinstein, Thomas M. Grogan

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

We have established a reproducible in vivo model of human multiple myeloma in the severe combined immunodeficiency (SCID) mouse using both the drug-sensitive 8226/S human myeloma cell line and the P-glycoprotein- expressing multidrug-resistant 8226/C IN subline. As demonstrated previously, the SCID mouse is well suited as a model for myeloma because: (a) human SCID xenografts are readily attained; (b) human myeloma xenografts are readily detected by their immunoglobulin secretion; and (c) differential therapy effects in drug-sensitive versus drug-resistant cell lines are readily demonstrable by monitoring mouse urinary human immunoglobulin output. In the current study, we have utilized this model to evaluate the in vivo efficacy of chemomodulators of P-glycoprotein-related multidrug resistance. In our initial experiments, doxorubicin alone was effective in treating the 8226/S human myeloma xenografts but had no effect on the drug-resistant 8226/C IN xenografts, in the absence of the chemosensitizing agent verapamil. In subsequent experiments, the combination of verapamil and doxorubicin resulted in both a decrease in human X light chain urinary excretion and an increase in survival of those animals bearing the 8226/C IN tumor. The median survival time of animals injected with 8226/C IN cells and subsequently treated with doxorubicin was 48.6 ± 7 days, which compared to a survival of 89.6 ±18 days in animals receiving the 8226/S cell line and treated with doxorubicin alone (P < 0.001). When verapamil was added to the treatment regimen of those animals bearing the 8226/C IN xenografts, there was a 179% increase in their life span (P <001), which corresponded with the observed decreased light chain in the urine. In animals receiving multiple courses of chemotherapy, an attenuated response to vera- clinical setting of human drug-resistant myeloma escape from chemosensitivity. The SCID human myeloma xenograft model thus offers a means of evaluating the in vivo efficacy and potential toxicities of new therapeutic approaches directed against P-glycoprotein in multidrug-resistant human myeloma.

Original languageEnglish (US)
Pages (from-to)1563-1570
Number of pages8
JournalClinical Cancer Research
Volume1
Issue number12
StatePublished - Aug 1 1995

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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