Molecular Biotechnology

, Volume 35, Issue 2, pp 185–197 | Cite as

Methods and goals for the use of in vitro and in vivo chemosensitivity testing

Review

Abstract

Sensitive, specific, and accurate methods to assay chemosensitivity are needed to (1) screen new therapeutic agents, (2) identify patterns of chemosensitivity for different tumor types, (3) establish patterns of cross-resistance and sensitivity in treatment of naïve and relapsing tumors, (4) identify genomic and proteomic profiles associated with sensivity, (5) correlate in vitro response with preclinical in vivo effects and clinical outcomes for a particular therapeutic agent, and (6) tailor chemotherapy regimens to individual patients. Various methods are available to achieve these end points, including several in vitro clonogenic and proliferation assays, cell metabolic activity assays, molecular assay to monitor expression of markers for responsiveness, drug resistance, and for induction of apoptosis, in vivo tumor growth and survival assays in metastatic and orthotopic models, and in vivo imaging assays. The advantages and disadvantages of the specific assays are discussed. A summary of research questions related to chemosensitivity testing is also included.

Index Entries

Dose-response curve IC50 values imaging metabolic assays molecular markers proliferation assays 

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References

  1. 1.
    Nagourney, R. A. 2006. Ex vivo programmed cell death and the prediction of response to chemotherapy. Curr. Treat. Options Oncol. 7, 103–110.PubMedCrossRefGoogle Scholar
  2. 2.
    Chow, K. U., Nowak, D., Kim, S. Z., et al. 2006. In vivo drug-response in patients with leukemic non-Hodgkin's lymphomas is associated with in vitro chemosensitivity and gene expression profiling. Pharmacol. Res. 53, 49–61.PubMedCrossRefGoogle Scholar
  3. 3.
    Noguchi, K., Iwahashi, M., Tani, M., et al. 2005. Evaluation of chemosensitivity testing with highly purified tumor cells in 435 patients with gastric carcinoma using an MTT assay. Anticancer Res. 25, 931–937.PubMedGoogle Scholar
  4. 4.
    Trojan, J., Kim, S. Z., Engels, K., Kriener, S., Mitrou, P. S., and Chow, K. U. 2005. In vitro chemosensitivity to gemcitabine, oxaliplatin and zoledronic acid predicts treatment response in metastatic gastric cancer. Anticancer Drugs 16, 87–91.PubMedCrossRefGoogle Scholar
  5. 5.
    Kaspers, G., Zwaan, C., Pieters, R., and Veerman, A. 1999. Cellular drug resistance in childhood acute myeloid leukemia. A mini-review with emphasis on cell culture assay. Adv. Exp. Med. Biol. 457, 415–421.PubMedGoogle Scholar
  6. 6.
    Robert, J. 1999. Chemosensitivity Testing: Prediction of response to anticancer drugs using in vitro assays. Electronic J. Oncol. 2, 198–210.Google Scholar
  7. 7.
    Bellamy, W. 1992. Prediction of response to drug therapy of cancer. A review of in vitro assay. Drugs 44, 690–708.PubMedGoogle Scholar
  8. 8.
    Gercel-Taylor, C., Ackermann, M., and Taylor, D. 2001. Evaluation of cell proliferation and cell death based assays in chemosensitivity testing. Anticancer Res. 21, 2761–2768.PubMedGoogle Scholar
  9. 9.
    Von Hoff, D., Clark, G., Stogill, B., et al. 1983. Prospective clinical trial of a human tumor cloning system. Cancer Res. 43.Google Scholar
  10. 10.
    Engblom, P., Rantanen, V., Kulmala, J., and Grenman, S. 1996. Paclitaxel and cisplatin sensitivity of ovarian carcinoma cell lines tested with a 96-well plate clonogenic assay. Anticancer Res. 16, 1743–1747.PubMedGoogle Scholar
  11. 11.
    Fiebig, H. H., Maier, A., and Burger, A. M. 2004. Clonogenic assay with, established human tumour xenografts: correlation of in vitro to in vivo activity as a basis for anticancer drug discovery. Eur. J. Cancer 40, 802–820.PubMedCrossRefGoogle Scholar
  12. 12.
    Dollner, R., Granzow, C., Neudert, M., and Dietz, A. 2006. Ex vivo chemosensitivity of head and neck carcinoma to cytostatic drug combinations. Anticancer Res. 26, 1651–1655.PubMedGoogle Scholar
  13. 13.
    Weisenthal, L., Marsden, J., Dill, P., and Macaluso, C. 1983. A novel dye exclusion method for testing in vitro chemosensitivity of human tumors. Cancer Res. 43, 749–757.PubMedGoogle Scholar
  14. 14.
    Kern, D., Drozemuller, C., Kennedy, M., et al. 1985. Development of a miniaturized improved nucleic acid precursor incorporation assay for chemosensitivity testing of human solid tumors. Cancer Res. 45, 5436–5441.PubMedGoogle Scholar
  15. 15.
    Sondak, V., Bertelson, C., Tanigawa, N., et al. 1984. Clinical correlations with chemosensitivities measured in a rapid thymidine incorporation assay. Cancer Res. 46, 1725–1728.Google Scholar
  16. 16.
    Kobayashi, H., Higashiyami, M., Minamigawa, K., et al. 2001. Examination of in vitro chemosensitivity test using collagen gel droplet culture method with colorimetric endpoint quantitation. Jpn. J. Cancer Res. 92, 203–210.PubMedGoogle Scholar
  17. 17.
    Kangas, L., Gronroos, M., and Nieminen, A. 1984. Bioluminesence of cellular ATP: a new method for evaluating cytotoxic agents in vitro. Med. Biol. 62, 338–343.PubMedGoogle Scholar
  18. 18.
    Csoka, K., Larsson, R., Tholander, B., Gerdin, E., de la Torre, M., and Nygren, P. 1994. Cytotoxic drug sensitivity testing of tumor cells from patients with ovarian carcinoma using the fluorometric microculture cytotoxicity assay (FMCA). Gynecol. Oncol. 54, 163–170.PubMedCrossRefGoogle Scholar
  19. 19.
    Rubinstein, L., Shoemaker, R., Pacell, K., Simon, R., and Tosini, S. 1990. Comparison of an in vitro anti-cancer drug screening data generated with a tetrazoilum assay versus a protein assay against a di verse panel of human tumor cells lines. J. Natl. Cancer Inst. 82, 1113–1118.PubMedCrossRefGoogle Scholar
  20. 20.
    Krasna, L., Netikova, I., Chaloupkova, A., et al. 2003. Assessment of in vitro drug resistance of human breast cancer cells subcultured from biopsy specimens. Anticancer Res. 23, 2593–2599.PubMedGoogle Scholar
  21. 21.
    Sevin, B., Peng, Z., Perras, J., Panalver, G., and Averette, H. 1988. Application of an ATP bioluminescence assay in human tumor chemosensitivity testing. Gynecol. Oncol. 31, 191–204.PubMedCrossRefGoogle Scholar
  22. 22.
    Andreotti, P., Gree, I., Kurbacher, C., et al. 1995. Chemosensitivity testing of human tumors using a microplate adenosine triphosphate luminescence assay: clinical correlation for cisplatin resistance of ovarian carcinoma. Cancer Res. 55, 5276–5282.PubMedGoogle Scholar
  23. 23.
    Steff, A., Fortin, M., Arguin, C., and Hugo, P. 2001. Detection of a decrease in green fluorescent protein fluorescence forthe monitoring of cell death: an assay amenable to high-throughput screening technologies. Cytometry. 45, 237–243.PubMedCrossRefGoogle Scholar
  24. 24.
    Waldenmaier, D. S., Babarina, A., and Kischkel, F. C. 2003. Rapid in vitro chemosensitivity analysis of human colon tumor cell lines. Toxicol. Appl. Pharmacol. 192, 237–245.PubMedCrossRefGoogle Scholar
  25. 25.
    Otto, A. M., Brischwein, M., Niendorf, A., Henning, T., Motrescu, E., and Wolf, B. 2003. Microphysicological testing for chemosensitivity of living tumor cells with multiparametric microsensor chips. Cancer Detect. Prev. 27, 291–296.PubMedCrossRefGoogle Scholar
  26. 26.
    Vistica, D., Skehan, P., Scudiero, D., et al. 1991. Tetrazolium-based assays for cellular viability: a critical examination of selected parameters affecting formazan production. Cancer Res. 51, 2515–2520.PubMedGoogle Scholar
  27. 27.
    Sargent, J. and Taylor, C. 1989. Appraisal of the MTT assay as a rapid test of chemosensitivity in acute myeloid leukemia. Brit. J. Cancer 60, 206–210.PubMedGoogle Scholar
  28. 28.
    Ross, D. D., Joneckis, C. C., Ordonez, J. V., et al. 1989. Estimation of cell survival by flow cytometric quantification of fluorescein diacetate/propidium iodide viable cell number. Cancer Res. 49, 3776–3782.PubMedGoogle Scholar
  29. 29.
    Proffitt, R. T., Tran, J. V., and Reynolds, C. P. 1996. A fluorescence digital image microscopy system for quantifying relative cell numbers in tissue culture plates. Cytometry 24, 204–213.PubMedCrossRefGoogle Scholar
  30. 30.
    Hoffman, R. 1991. Three-dimensional histoculture: origins and applications in cancer research. Cancer Cells 3, 86–92.PubMedGoogle Scholar
  31. 31.
    Singh, B., Li, R., Xyu, L., et al. 2002. Prediction of survival in patients with head and neck cancer using the histoculture drug response assay. Head Neck 24, 437–442.PubMedCrossRefGoogle Scholar
  32. 32.
    Meitner, P. 1991. The fluorescence cytoprint assay: a new approach to in vitro chemosensitivity testing. Oncology 5, 75–81.PubMedGoogle Scholar
  33. 33.
    Kern, D. and Weisenthal, L. 1990. Highly specific prediction of antineoplastic drug resistance with an in vitro assay using supra-pharmacologic drug exposures. J. Natl. Cancer Inst. 82, 582–588.PubMedCrossRefGoogle Scholar
  34. 34.
    Haroun, R., Clatterbuck, R., Gibbons, M., et al. 2002. Extreme drug resistance in primary brain tumors: in vitro analysis of 64 resection specimens. J. Neurooncol. 58, 115–123.PubMedCrossRefGoogle Scholar
  35. 35.
    Fenech, M. 2000. The in vitro micronucleus technique. Mutation Res. 455, 81–95.PubMedGoogle Scholar
  36. 36.
    Fruhauf, J. and Bosanquet, A. 1993. In vitro determination of drug response: A discussion of clinical applications. PPO Updates 7, 1–21.Google Scholar
  37. 37.
    Reynolds, C. P. and Maurer, B. J. 2005. Evaluating response to antineoplastic drug combinations in tissue culture models. Methods Mol. Med. 110, 173–183.PubMedGoogle Scholar
  38. 38.
    Clarke, R. 1996. Human breast cancer cell line xenografts as models of brest cancer the immunobiologies of recipient mice and the characteristics of several tumorigenic lines. Breast Cancer Res. Treat. 39, 69–86.PubMedCrossRefGoogle Scholar
  39. 39.
    Hoffman, R. 1999. Orthotopic metastatic mouse models for anticancer drug discovery and evaluation: a bridge to the clinic. Invest. New Drugs 17, 343–359.PubMedCrossRefGoogle Scholar
  40. 40.
    Price, J. 1996. Metastasis from human breast cancer cell lines. Breast Cancer Res. Treat. 39, 93–102.PubMedCrossRefGoogle Scholar
  41. 41.
    Konovalova, N., Iatchkovskaya, R., Ganieva, L., et al. 1991. Subrenal capsule assay of human tumor chemosensitivity. Neoplasma 38, 275–284.PubMedGoogle Scholar
  42. 42.
    Tomayko, M. and Reynolds, C. 1989. Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother. Pharmacol. 24, 148–154.PubMedCrossRefGoogle Scholar
  43. 43.
    Heitjan, D., Manni, A. and Santen, R. 1993. Statistical analysis of in vivo tumor growth experiments. Cancer Res. 53, 6042–6050.PubMedGoogle Scholar
  44. 44.
    Gibbs, J., Slocum, H., Cao, S. and Rustum, Y. 1999. Image analysis for quantitation of solid tumor drug sensitivity. Int. J. Surg. Invest. 1, 133–138.Google Scholar
  45. 45.
    Kubota, K. 2001. From tumor biology to clinical PET: a review of positron emission tomography (PET) in oncology. Ann. Nucl. Med. 15, 471–486.PubMedCrossRefGoogle Scholar
  46. 46.
    Belhocine, T., Steinmetz, N., Hustinx, R., et al. 2002. Increased uptake of the apoptosis imaging agent (99m)Tc recombinant human Annexin V in human tumors after one course of chemotherapy as a predictor of tumor response and patient prognosis. Clin. Cancer Res. 8, 2766–2774.PubMedGoogle Scholar
  47. 47.
    Mazurchuk, R., Glaves, D., and Raghavan, D. 1997. Magnetic resonance imaging of response to chemotherapy in orthotopic xenografts of human bladder cancer. Clin. Cancer Res. 3, 1635–1641.PubMedGoogle Scholar
  48. 48.
    Nakanishi, H., Mochizuki, Y., Kodera, Y., et al. 2003. Chemosensitivity of peritoneal micrometastases as evaluated using green fluorescence protein (GFP)-tagged human gastric cancer cell line. Cancer Sci. 94, 112–118.PubMedCrossRefGoogle Scholar
  49. 49.
    Ring, A., Smith, I. E., and Dowsett, M. 2004. Circulating tumour cells in breast cancer. Lancet Oncol. 5, 79–88.PubMedCrossRefGoogle Scholar
  50. 50.
    Allard, W. J., Matera, J., Miller, M. C., et al. 2004. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin. Cancer Res. 10, 6897–6904.PubMedCrossRefGoogle Scholar
  51. 51.
    Tewari, K. and Manetta, A. 1999. In vitro chemosensitivity testing and mechanisms of drug resistance. Curr. Oncol. Rep. 1, 77–84.PubMedCrossRefGoogle Scholar
  52. 52.
    el-Deiry, W. S. 1997. Role of oncogenes in resistance and killing by cancer therapeutic agents. Curr. Opin. Oncol. 9, 79–87.PubMedGoogle Scholar
  53. 53.
    Fan, S., el-Deiry, W., Bae, I., et al. 1994. p53 gene mutations are associated with decreased sensitivity of human lymphoma cells to DNA damaging agents. Cancer Res, 54, 5824–5830.PubMedGoogle Scholar
  54. 54.
    Bosken, C., Wei, Q., Amos, C., and Spitz, M. 2002. An analysis of DNA repair as a determinant of survival in patients with non-small-cell lung cancer. J. Natl. Cancer Inst. 94, 1091–1099.PubMedGoogle Scholar
  55. 55.
    Zunino, F., Perego, P., Pilotti, S., and Pratesi, G. 1997. Role of apoptotic response in cellular resistance to cytotoxic agents. Pharmacol. Ther. 76, 177–185.PubMedCrossRefGoogle Scholar
  56. 56.
    Wang, Y., Ashkenazi, Y., and Bachrach, U. 1999. In vitro chemosensitivity of hematological cancers: Immunohistochemical detection of ornithine decarboxylase. Anticancer Drugs 10, 797–805.PubMedCrossRefGoogle Scholar
  57. 57.
    Park, K., Rha, S., Kim, C., et al. 1998. Telomerase activity and telomere lengths in various cell lines: changes of telomerase activity can be another method for chemosensitivity evaluation. Int. J. Oncol. 13, 489–495.PubMedGoogle Scholar
  58. 58.
    Modrak, D., Rodriguez, M., Goldenberg, D., Lew, W., and Blumenthall, R. 2002. Sphingomyelin enhances chemotherapy efficacy and increases apoptosis in human colonic tumor xenografts. Int. J. Oncol. 20, 379–384.PubMedGoogle Scholar
  59. 59.
    Epstein, R. 1990. Drug-induced DNA damage and tumor chemosensitivity. J. Clin. Oncol. 8, 2062–2084.PubMedGoogle Scholar
  60. 60.
    Xia, F., and Powell, S. 2002. The molecular basis of radiosensitivity and chemosensitivity in the treatment of breast cancer. Semin. Radiat. Oncol. 12, 296–304.PubMedCrossRefGoogle Scholar
  61. 61.
    Manahan, K., Taylor, D., and Gercel-Taylor, C. 2001. Clonal heterogeneity of p53 mutations in ovarian cancer. Int. J. Oncol. 19, 387–394.PubMedGoogle Scholar
  62. 62.
    Granjean, F., Bremaud, L., Verdier, M., Robert, J., and Ratinaud, M. 2001. Sequential gene expression of P-glycoprotein (P-gp), multidrug resisatnce associated protein (MRP) and lung resistance protein: functional activity of P-gp and MRP present in the doxorubicin-resistant human K562 cell lines. Anti-cancer Drugs 12, 247–258.CrossRefGoogle Scholar
  63. 63.
    Michieli, M., Damiani, D., Ermacora, A., et al. 2000. P-glycoprotein (PGP), lung resistance-related protein (LRP) and multidrug resisatnce-associated protein (MRP) expression in acute promyelocytic leukemia. Br. J. Haematol. 108, 703–709.PubMedCrossRefGoogle Scholar
  64. 64.
    Pallis, M., Turzanski, J., Langabeer, S., and Russell, N. 1999. Reproducible flow cytometric methodology for measuring multidrug resistance in leukaemic blasts. Adv. Exp. Med. Biol. 457, 77–88.PubMedGoogle Scholar
  65. 65.
    Pall, G., Spitaler, M., Hofmann, J., Thaler, J., and Ludescher, C. 1997. Multidrug resistance in acute leukemia: a comparison of different diagnostic methods. Leukemia 11, 1067–1072.PubMedCrossRefGoogle Scholar
  66. 66.
    Singh, N. 2000. A simple method for accurate estimation of apoptotic cells. Exp. Cell Res. 256, 328–337.PubMedCrossRefGoogle Scholar
  67. 67.
    Munshi, A., McDonnell, T., and Meyn, R. 2002. Chemotherapeutic agents enhance TRAIL-induced apoptosis in prostate cancer cells. Cancer Chemother. Pharmacol. 50, 46–52.PubMedCrossRefGoogle Scholar
  68. 68.
    Maciorowski, Z., Klijanienko, J., Padoy, E., et al. 2001. Comparative image and flow cytometric TUNEL analysis of fine needle samples of breast carcinoma. Cytometry 46, 150–156.PubMedCrossRefGoogle Scholar
  69. 69.
    Ogata, S., Okumura, K., and Taguchi, H. 2000. A simple and rapid method for the detection of poly(ADP-ribose) by flow cytometry. Biosci. Biotechnol. Biochem. 64, 510–515.PubMedCrossRefGoogle Scholar
  70. 70.
    Nita, M., Nagawa, H., Tominago, O., et al. 1998. 5-Fluorouracil induces apoptosis in human colon cancer cell lines with modulation of Bcl-2 family proteins. Br. J. Cancer 78, 986–992.PubMedGoogle Scholar
  71. 71.
    Smith, D., Gao, G., Zhang, X., Wang, G., and Dou, Q. 2000. Regulation of tumor cell apoptotic sensitivity during the cell cycle (review). Int. J. Mol. Med. 6, 503–507.PubMedGoogle Scholar
  72. 72.
    Sonneveld, P. 2000. Multidrug resistance in hematological malignancies. J. Intern. Med. 247, 521–534.PubMedGoogle Scholar
  73. 73.
    Staunton, J., Slonim, D., Coller, H., et al. 2001. Chemosensitivity prediction by transcriptional profiling. Proc. Natl. Acad. Sci. USA 98, 10787–10792.PubMedCrossRefGoogle Scholar
  74. 74.
    Bao, L., and Sun, Z. 2002. Identifying genes related to drug anticancer mechanisms using support vector machine. FEBS Lett. 521, 109–114.PubMedCrossRefGoogle Scholar
  75. 75.
    McLeod, H. 2002. Individualized cancer therapy: molecular approaches to the prediction of tumor response. Expert Rev. Anticancer Ther. 2, 113–119.PubMedCrossRefGoogle Scholar
  76. 76.
    Amundson, S., Myers, T., Scudiero, D., Kitada, S., Reed, J., and Fornace, A. 2000. An informatics approach identifying markers of chemosensitivity in human cancer cell lines. Cancer Res. 60, 6101–6110.PubMedGoogle Scholar
  77. 77.
    Alizadeh, A., Eisen, M., and Dasvis, R. 2000. Distinct types of diffuse large B-cell lympoma identified by gene expression profiling. Nature 403, 503–511.PubMedCrossRefGoogle Scholar
  78. 78.
    Kihara, C., Tsunoda, T., Tanaka, T., et al. Prediction of sensitivity of esophageal tumors to adjuvant chemotherapy by cDNA microarray analysis of gene-expression profiles. Cancer Res., 61, 6474–6479.Google Scholar
  79. 79.
    Sotirious, C., Powles, T., Dowsett, M., et al. 2002. Gene expression profiles derived from fine needle aspiration correlate with response to systemic chemotherapy in breast cancer. Breast Cancer Res. 4, R3.CrossRefGoogle Scholar
  80. 80.
    Stein, W. D., Litman, T., Fojo, T., and Bates, S. E. 2004. A Serial Analysis of Gene Expression (SAGE) database analysis of chemosensitivity: comparing solid tumors with cell lines and comparing solid tumors from different tissue origins. Cancer Res. 64, 2805–2816.PubMedCrossRefGoogle Scholar
  81. 81.
    Poland, J., Schadendorf, D., Lage, H., Schnolzer, M., Celis, J., and Siha, P. 2002. Study of therapy resistance in cancer cells with functional proteome analysis. Clin. Chem. Lab. Med. 40, 221–234.PubMedCrossRefGoogle Scholar
  82. 82.
    Aschele, C., Debernardis, D., Casazza, S., et al. 1999. Immunohistochemical quantitation of thymidylate synthase expression in colorectal cancer metastases predicts for clinical outcome to fluorouracil-based chemotherapy. J. Clin. Oncol. 17, 1760–1770.PubMedGoogle Scholar
  83. 83.
    Bachrach, U., and Wang, Y. 2003. In vitro chemosensitivity testin of hematological cancer patients: detection of ornithine decarboxylase. Rec Results Cancer Res. 161, 62–70.Google Scholar
  84. 84.
    Konecny, G., Fritz, M., Untch, M., et al. 2001. Her-2/neu overexpression and in vitro chemosensitivity to CMF and FEC in primary breast cancer. Breast Cancer Res. Treat. 69, 53–63.PubMedCrossRefGoogle Scholar
  85. 85.
    Yang, Q., Sakurai, T., Yoshimura, G., et al. 2000. Overexpression of p27 protein in human breast cancer correlates with in vitro resistance to doxorubicin and mitomycin C. Anticancer Res. 20, 4319–4322.PubMedGoogle Scholar
  86. 86.
    Yang, Q., Sakurai, T., Yoshimura, G., et al. 2000. Expression of Bcl-2 but not Bax or p53 correlates with in vitro resisatnce to a series of anticancer drugs in breast carcinoma. Breast Cancer Res. Treat. 61, 211–216.PubMedCrossRefGoogle Scholar
  87. 87.
    Rozan, S., Vincent-Salomon, A., Zafrani, B., et al. 1998. No significant predictive value of c-erbB-2 or p53 expression regarding sensitivity to primary chemotherapy or radiotherapy in breast cancer. Int. J. Cancer 79, 27–33.PubMedCrossRefGoogle Scholar
  88. 88.
    Ginestier, C., Charafe-Jauffret, E., Bertucci, F., et al. 2002. Distinct and complementary information provided by use of tissue and DNA microarrays in the study of breast tumor markers. Am. J. Pathol. 161, 1223–1233.PubMedGoogle Scholar
  89. 89.
    Jones, M., Krutzsch, H., Shu, H., Zhao, Y., Liotta, L., Kohn, E., and Petricoin, E. R. 2002. Proteomic analysis and identification of new biomarkers and therapeutic targets for invasive ovarian cancer. Proteomics 2, 76–84.PubMedCrossRefGoogle Scholar
  90. 90.
    Schrag, D., Garewal, H. S., Burstein, H. J., Samson, D. J., Von Hoff, D. D., and Somerfield, M. R. 2004. American Society of Clinical Oncology Technology Assessment: chemotherapy sensitivity and resistance assays. J. Clin. Oncol. 22, 3631–3638.PubMedCrossRefGoogle Scholar
  91. 91.
    Konecny, G., Untch, M., Slamon, D., et al. 2001. Drug interactions and cytotoxic effects of paclitaxel in combination withc arboplatin, epirubicin, gemcitabine, or vinorelbine in breast cancer cell lines and tumor samples. Breast Cancer Res. Treat. 67, 223–233.PubMedCrossRefGoogle Scholar
  92. 92.
    Lopez, A., Pegram, M., Slamon, D., and Landaw, E. 1999. A model-based approach for assessing in vivo combination therapy interactions. Proc. Natl. Acad. Sci. USA 96, 13023–13028.PubMedCrossRefGoogle Scholar
  93. 93.
    Heim, M., Eberhardt, W., Seeber, S., and Muller, M. 2000. Differential modulation of chemosensitivity to alkylkating agents and platinum compounds by DNA repair modulators in human lung cancer cell lines. J. Cancer Res. Clin. Oncol. 126, 198–204.PubMedCrossRefGoogle Scholar
  94. 94.
    Kondratov, R., Komarov, P., Becker, Y., Ewenson, A., and Gudkov, A. 2001. Small molecules that dramatically alter multidrug resistance phenotype by modulating the substrate specificity of P-glycoprotein. Proc. Natl. Acad. Sci. USA 98, 14078–14083.PubMedCrossRefGoogle Scholar
  95. 95.
    Henewisch-Becker, S. 1996. MDR1 reversal: criteria for clinical trials designed to overcome the multidrug resistance phenotype. Leukemia 10, S32-S38.Google Scholar
  96. 96.
    Levi, F., Giacchetti, S., Zidani, R., et al. 2001. Chremotherapy of colorectal cancer metastases. Hepatogastroenterology 48, 320–322.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 2007

Authors and Affiliations

  1. 1.Garden State Cancer CenterBellevilleUSA

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