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Cell Cycle Checkpoint Models for Cellular Pharmacology of Paclitaxel and Platinum Drugs

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Abstract

A pharmacokinetic–pharmacodynamic mathematical model is developed for cellular pharmacology of chemotherapeutic drugs for which the decisive step towards cell death occurs at a point in the cell cycle, presumably corresponding to a cell cycle checkpoint. For each cell, the model assumes a threshold level of some intracellular species at that checkpoint, beyond which the cell dies. The threshold level is assumed to have a log-normal distribution in the cell population. The kinetics of formation of the lethal intracellular species depends on the drug, and on the cellular pharmacokinetics and binding kinetics of the cell. Specific models are developed for paclitaxel and for platinum drugs (cisplatin, oxaliplatin and carboplatin). In the case of paclitaxel, two separate mechanisms of cell death necessitate a model that accounts for two checkpoints, with different intracellular species. The model was tested on a number of in vitro cytotoxicity data sets for these drugs, and found overall to give significantly better fits than previously proposed cellular pharmacodynamic models. It provides an explanation for the asymptotic convergence of dose-response curves as exposure time becomes long.

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References

  1. E. Briasoulis, V. Karavasilis, E. Tzamakou, C. Haidou, C. Piperidou, and N. Pavlidis. Pharmacodynamics of non-break weekly paclitaxel (Taxol) and pharmacokinetics of Cremophor-EL vehicle: results of a dose-escalation study. Anticancer Drugs 13(5):481–489 (2002).

    Article  PubMed  CAS  Google Scholar 

  2. D. Schrag, H. S. Garewal, H. J. Burstein, D. J. Samson, D. D. Von Hoff, and M. R. Somerfield. American Society of Clinical Oncology technology assessment: chemotherapy sensitivity and resistance assays. J. Clin. Oncol. 22(17):3631–3638 (2004).

    Article  PubMed  CAS  Google Scholar 

  3. A. W. El-Kareh, and T. W. Secomb. Theoretical analyses and simulations of anticancer drug delivery. In D. M. Brown (ed.), Drug Delivery Systems in Cancer Therapy, Humana Press, Clifton, NJ, 2003, pp. 25–41.

    Chapter  Google Scholar 

  4. H. Eichholtz-Wirth. Dependence of the cytostatic effect of adriamycin on drug concentration and exposure time in vitro. Br. J. Cancer 41(6):886–891 (1980).

    PubMed  CAS  Google Scholar 

  5. S. Ozawa, Y. Sugiyama, Y. Mitsuhashi, T. Kobayashi, and M. Inaba. Cell killing action of cell cycle phase-non-specific antitumor agents is dependent on concentration–time product. Cancer Chemother. Pharmacol. 21(3):185–190 (1988).

    Article  PubMed  CAS  Google Scholar 

  6. A. W. El Kareh, and T. W. Secomb. Two-mechanism peak concentration model for cellular pharmacodynamics of doxorubicin. Neoplasia 7(7):705–713 (2005).

    Article  PubMed  CAS  Google Scholar 

  7. H. E. Skipper. The effects of chemotherapy on the kinetics of leukemic cell behavior. Cancer Res. 25(9):1544–1550 (1965).

    PubMed  CAS  Google Scholar 

  8. D. J. Adams. In Vitro pharmacodynamic assay for cancer drug development—application to crisnatol, a new Dna intercalator. Cancer Res. 49(23):6615–6620 (1989).

    PubMed  CAS  Google Scholar 

  9. N. J. Millenbaugh, M. G. Wientjes, and J. L. S. Au. A pharmacodynamic analysis method to determine the relative importance of drug concentration and treatment time on effect. Cancer Chemother. Pharmacol. 45(4):265–272 (2000).

    Article  PubMed  CAS  Google Scholar 

  10. L. M. Levasseur, H. K. Slocum, Y. M. Rustum, and W. R. Greco. Modeling of the time-dependency of in vitro drug cytotoxicity and resistance. Cancer Res. 58(24):5749–5761 (1998).

    PubMed  CAS  Google Scholar 

  11. S. N. Gardner. A mechanistic, predictive model of dose-response curves for cell cycle phase-specific and -nonspecific drugs. Cancer Res. 60(5):1417–1425 (2000).

    PubMed  CAS  Google Scholar 

  12. A. W. El-Kareh, and T. W. Secomb. A mathematical model for cisplatin cellular pharmacodynamics. Neoplasia 5(2):161–169 (2003).

    PubMed  CAS  Google Scholar 

  13. J. L. S. Au, D. Li, Y. B. Gan, X. Gao, A. L. Johnson, J. Johnston, et al. Pharmacodynamics of immediate and delayed effects of paclitaxel: role of slow apoptosis and intracellular drug retention. Cancer Res. 58(10):2141–2148 (1998).

    PubMed  CAS  Google Scholar 

  14. R. E. Eliaz, S. Nir, C. Marty, and F. C. Szoka. Determination and modeling of kinetics of cancer cell killing by doxorubicin and doxorubicin encapsulated in targeted liposomes. Cancer Res. 64(2):711–718 (2004).

    Article  PubMed  CAS  Google Scholar 

  15. P. Vrignaud, D. Londosgagliardi, and J. Robert. Cellular pharmacology of doxorubicin in sensitive and resistant rat glioblastoma cells in culture. Oncology 43(1):60–66 (1986).

    Article  PubMed  CAS  Google Scholar 

  16. H. Minderman, S. S. Cao, and Y. M. Rustum. Rational design of irinotecan administration based on preclinical models. Oncology (New York) 12(8):22–30 (1998).

    CAS  Google Scholar 

  17. P. G. Parsons. Dependence on treatment time of melphalan resistance and Dna cross-linking in human-melanoma cell-lines. Cancer Res. 44(7):2773–2778 (1984).

    PubMed  CAS  Google Scholar 

  18. E. D. Lobo, and J. P. Balthasar. Pharmacodynamic modeling of chemotherapeutic effects: Application of a transit compartment model to characterize methotrexate effects in vitro. AAPS PharmSci 4(4):42–44 (2002).

    Article  Google Scholar 

  19. Y. Miyagi, K. Kawanishi, Y. Miyagi, S. Yamada, J. Yamamoto, J. Kodama, et al. Cytocidal effect and DNA damage of nedaplatin: a mathematical model and analysis of experimental data. Cancer Chemother. Pharmacol. 47(3):229–235 (2001).

    Article  PubMed  CAS  Google Scholar 

  20. M. Simeoni, P. Magni, C. Cammia, G. De Nicolao, V. Croci, E. Pesenti, et al. Predictive pharmacokinetic–pharmacodynamic modeling of tumor growth kinetics in xenograft models after administration of anticancer agents. Cancer Res. 64(3):1094–1101 (2004).

    Article  PubMed  CAS  Google Scholar 

  21. M. A. Shah, and G. K. Schwartz. Cell cycle-mediated drug resistance: an emerging concept in cancer therapy. Clin. Cancer Res. 7(8):2168–2181 (2001).

    PubMed  CAS  Google Scholar 

  22. D. L. Evans, M. Tilby, and C. Dive. Differential sensitivity to the induction of apoptosis by cisplatin in proliferating and quiescent immature rat thymocytes is independent of the levels of drug accumulation and Dna adduct formation. Cancer Res. 54(6):1596–1603 (1994).

    PubMed  CAS  Google Scholar 

  23. R. C. Jackson. The problem of the quiescent cancer cell. Adv. Enzyme Regul. 29:27–46 (1989).

    Article  PubMed  CAS  Google Scholar 

  24. M. T. Dimancheboitrel, C. Garrido, and B. Chauffert. Kinetic resistance to anticancer agents. Cytotechnology 12(1–3):347–356 (1993).

    Article  CAS  Google Scholar 

  25. S. Masunaga, K. Ono, H. Hori, M. Akaboshi, K. Kawai, and M. Suzuki, et al. Enhancement of cisplatin sensitivity of quiescent cells in solid tumors by combined treatment with tirapazamine and low-temperature hyperthermia. Radiat. Med. 16(6):441–448 (1998).

    PubMed  CAS  Google Scholar 

  26. A. Swierniak, A. Polanski, and M. Kimmel. Optimal control problems arising in cell-cycle-specific cancer chemotherapy. Cell Prolif. 29(3):117–139 (1996).

    Article  PubMed  CAS  Google Scholar 

  27. W. J. Jusko. Pharmacodynamic model for cell-cycle-specific chemotherapeutic agents. J. Pharmacokinet. Biopharm. 1(3):175–200 (1973).

    Article  CAS  Google Scholar 

  28. S. Ozawa, Y. Sugiyama, J. Mitsuhashi, and M. Inaba. Kinetic-analysis of cell killing effect induced by cytosine-arabinoside and cisplatin in relation to cell-cycle phase specificity in human-colon cancer and Chinese-hamster cells. Cancer Res. 49(14):3823–3828 (1989).

    PubMed  CAS  Google Scholar 

  29. K. R. Fister, and J. C. Panetta. Optimal control applied to cell-cycle-specific cancer chemotherapy. SIAM J. Appl. Math. 60(3):1059–1072 (2000).

    Article  Google Scholar 

  30. K. L. Donaldson, G. L. Goolsby, and A. F. Wahl. Cytotoxicity of the anticancer agents cisplatin and taxol during cell-proliferation and the cell-cycle. Int. J. Cancer 57(6):847–855 (1994).

    Article  PubMed  CAS  Google Scholar 

  31. G. Sena, C. Onado, P. Cappella, F. Montalenti, and P. Ubezio. Measuring the complexity of cell cycle arrest and killing of drugs: kinetics of phase-specific effects induced by Taxol. Cytometry 37(2):113–124 (1999).

    Article  PubMed  CAS  Google Scholar 

  32. M. O. Trielli, P. R. Andreassen, F. B. Lacroix, and R. L. Margolis. Differential taxol-dependent arrest of transformed and nontransformed cells in the G1 phase of the cell cycle, and specific-related mortality of transformed cells. J. Cell Biol. 135(3):689–700 (1996).

    Article  PubMed  CAS  Google Scholar 

  33. V. Troger, J. L. Fischel, P. Formento, J. Gioanni, and G. Milano. Effects of prolonged exposure to cisplatin on cytotoxicity and intracellular drug concentration. Eur. J. Cancer 28(1):82–86 (1992).

    Article  PubMed  CAS  Google Scholar 

  34. H. J. Kuh, S. H. Jang, M. G. Wientjes, and J. L. Au. Computational model of intracellular pharmacokinetics of paclitaxel. J. Pharmacol. Exp. Ther. 293(3):761–770 (2000).

    PubMed  CAS  Google Scholar 

  35. A. Riccardi, T. Servidei, A. Tornesello, P. Puggioni, S. Mastrangelo, C. Rumi, et al. Cytotoxicity of paclitaxel and docetaxel in human neuroblastoma cell-lines. Eur. J. Cancer 31A(4):494–499 (1995).

    Article  PubMed  CAS  Google Scholar 

  36. S. B. Hassan, E. Jonsson, R. Larsson, and M. O. Karlsson. Model for time dependency of cytotoxic effect of CHS 828 in vitro suggests two different mechanisms of action. J. Pharmacol. Exp. Ther. 299(3):1140–1147 (2001).

    PubMed  CAS  Google Scholar 

  37. K. L. Donaldson, G. Goolsby, P. A. Kiener, and A. F. Wahl. Activation of P34(Cdc2) coincident with taxol-induced apoptosis. Cell Growth Differ. 5(10):1041–1050 (1994).

    PubMed  CAS  Google Scholar 

  38. K. Torres, and S. B. Horwitz. Mechanisms of taxol-induced cell death are concentration dependent. Cancer Res. 58(16):3620–3626 (1998).

    PubMed  CAS  Google Scholar 

  39. D. H. Kern, C. R. Morgan, and S. U. Hildebrandzanki. In Vitro pharmacodynamics of 1-beta-D-arabinofuranosylcytosine—synergy of antitumor-activity with cis-diamminedichloroplatinum(Ii). Cancer Res. 48(1):117–121 (1988).

    PubMed  CAS  Google Scholar 

  40. S. Hector, W. Bolanowska-Higdon, J. Zdanowicz, S. Hitt, and L. Pendyala. In vitro studies on the mechanisms of oxaliplatin resistance. Cancer Chemother. Pharmacol. 48(5):398–406 (2001).

    Article  PubMed  CAS  Google Scholar 

  41. M. Mishima, G. Samimi, A. Kondo, X. Lin, and S. B. Howell. The cellular pharmacology of oxaliplatin resistance. Eur. J. Cancer. 38(10):1405–1412 (2002).

    Article  PubMed  CAS  Google Scholar 

  42. S. P. Binks, and M. Dobrota. Kinetics and mechanism of uptake of platinum-based pharmaceuticals by the rat small-intestine. Biochem. Pharmacol. 40(6):1329–1336 (1990).

    Article  PubMed  CAS  Google Scholar 

  43. A. Ghezzi, M. Aceto, C. Cassino, E. Gabano, and D. Osella. Uptake of antitumor platinum(II)-complexes by cancer cells, assayed by inductively coupled plasma mass spectrometry (ICP-MS). J. Inorg. Biochem. 98(1):73–78 (2004).

    Article  PubMed  CAS  Google Scholar 

  44. E. Pereira-Maia, and A. Garnier-Suillerot. Impaired hydrolysis of cisplatin derivatives to aquated species prevents energy-dependent uptake in GLC4 cells resistant to cisplatin. J. Biol. Inorg. Chem. 8(6):626–634 (2003).

    Article  PubMed  CAS  Google Scholar 

  45. H. T. Rupniak, R. D. Whelan, and B. T. Hill. Concentration and time-dependent inter-relationships for antitumour drug cytotoxicities against tumour cells in vitro. Int. J. Cancer 32(1):7–12 (1983).

    Article  PubMed  CAS  Google Scholar 

  46. N. Kurihara, T. Kubota, Y. Hoshiya, Y. Otani, K. Kumai, and M. Kitajima. Antitumor activity of cis-diamminedichloroplatinum (II) depends on its time x concentration product against human gastric cancer cell lines in vitro. J. Surg. Oncol. 60(4):238–241 (1995).

    Article  PubMed  CAS  Google Scholar 

  47. M. Kornmann, H. Fakler, U. Butzer, H. G. Beger, and K. H. Link. Oxaliplatin exerts potent in vitro cytotoxicity in colorectal and pancreatic cancer cell lines and liver metastases. Anticancer Res. 20(5A):3259–3264 (2000).

    PubMed  CAS  Google Scholar 

  48. M. Q. Mohammed, and S. Retsas. Oxaliplatin is active in vitro against human melanoma cell lines: comparison with cisplatin and carboplatin. Anticancer Drugs 11(10):859–863 (2000).

    Article  PubMed  CAS  Google Scholar 

  49. K. W. Vugrin, L. P. Swiler, R. M. Roberts, N. J. Stucky-Mack, and S. P. Sullivan. Confidence region estimation techniques for nonlinear regression: three case studies. SAND2005–6893. 1–10–2005. Albuquerque NM, Sandia National Laboratories. Sandia Report.

  50. D. R. Siwak, S. Shishodia, B. B. Aggarwal, and R. Kurzrock. Curcumin-induced antiproliferative and proapoptotic effects in melanoma cells are associated with suppression of I kappa B kinase and nuclear factor KB activity and are independent of the B-Raf/mitogen-activated/extracellular signal-regulated protein kinase pathway and the Akt pathway. Cancer 104(4):879–890 (2005).

    Article  PubMed  CAS  Google Scholar 

  51. A. Photiou, M. N. Sheikh, D. Bafaloukos, and S. Retsas. Antiproliferative activity of vinorelbine (navelbine) against 6 human-melanoma cell-lines. J. Cancer Res. Clin. Oncol. 118(4):249–254 (1992).

    Article  PubMed  CAS  Google Scholar 

  52. M. Derenzini, L. Montanaro, D. Trere, A. Chilla, P. L. Tazzari, F. Dall’Olio, et al. Thymidylate synthase protein expression and activity are related to the cell proliferation rate in human cancer cell lines. J. Clin. Pathol.: Mol. Pathol. 55(5):310–314 (2002).

    CAS  Google Scholar 

  53. T. Ma, Z. G. Zhu, Y. B. Ji, Y. Zhang, Y. Y. Yu, B. Y. Liu, et al. Correlation of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase with sensitivity of gastrointestinal cancer cells to 5-fluorouracil and 5-fluoro-2′-deoxyuridine. World J. Gastroenterol. 10(2):172–176 (2004).

    PubMed  CAS  Google Scholar 

  54. S. Akiyama, H. Amo, T. Watanabe, M. Matsuyama, J. Sakamoto, M. Imaizumi, et al. Characteristics of 3 human gastric-cancer cell-lines, Nu-Gc-2, Nu-Gc-3 and Nu-Gc-4. Jpn. J. Surg. 18(4):438–446 (1988).

    Article  PubMed  CAS  Google Scholar 

  55. R. T. Morgan, L. K. Woods, G. E. Moore, L. A. Quinn, L. Mcgavran, and S. G. Gordon. Human cell-line (Colo 357) of metastatic pancreatic adenocarcinoma. Int. J. Cancer 25(5):591–598 (1980).

    Article  PubMed  CAS  Google Scholar 

  56. K. Yao, J. A. Gietema, S. Shida, M. Selvakumaran, X. Fonrose, N. B. Haas, et al. In vitro hypoxia-conditioned colon cancer cell lines derived from HCT116 and HT29 exhibit altered apoptosis susceptibility and a more angiogenic profile in vivo. Br. J. Cancer 93(12):1356–1363 (2005).

    Article  PubMed  CAS  Google Scholar 

  57. Z. H. Chen, O. I. Olopade, and T. M. Savarese. Expression of methylthioadenosine phosphorylase cDNA in p16(-), MTAP(-) malignant cells: Restoration of methylthioadenosine phosphorylase-dependent salvage pathways and alterations of sensitivity to inhibitors of purine de novo synthesis. Mol. Pharmacol. 52(5):903–911 (1997).

    PubMed  CAS  Google Scholar 

  58. K. A. Tacka, D. Szalda, A. K. Souid, J. Goodisman, and J. C. Dabrowiak. Experimental and theoretical studies on the pharmacodynamics of cisplatin in Jurkat cells. Chem. Res. Toxicol. 17(11):1434–1444 (2004).

    Article  PubMed  CAS  Google Scholar 

  59. L. B. Sheiner, and S. L. Beal. Some suggestions for measuring predictive performance. J. Pharmacokinet. Biopharm. 9(4):503–512 (1981).

    Article  PubMed  CAS  Google Scholar 

  60. S. H. Tseng, M. S. Bobola, M. S. Berger, and J. R. Silber. Characterization of paclitaxel (Taxol) sensitivity in human glioma- and medulloblastoma-derived cell lines. Neuro-oncol. 1(2):101–108 (1999).

    PubMed  CAS  Google Scholar 

  61. M. J. P. Welters, A. M. J. FichtingerSchepman, R. A. Baan, M. A. J. A. Hermsen, W. J. F. VanderVijgh, J. Cloos, et al. Relationship between the parameters cellular differentiation, doubling time and platinum accumulation and cisplatin sensitivity in a panel of head and neck cancer cell lines. Int. J. Cancer 71(3):410–415 (1997).

    Article  PubMed  CAS  Google Scholar 

  62. M. Jackel, and P. Kopfmaier. Influence of cisplatin on cell-cycle progression in xenografted human head and neck carcinomas. Cancer Chemother. Pharmacol. 27(6):464–471 (1991).

    Article  PubMed  CAS  Google Scholar 

  63. M. C. Jackel, R. TauschTreml, and P. Kopfmaier. Cytokinetic effects of cisplatin on diverse human head and neck carcinomas in vitro: dependence on the tumor sensitivity to cisplatin. J. Cancer Res. Clin. Oncol. 122(10):596–602 (1996).

    Article  PubMed  CAS  Google Scholar 

  64. E. Pasquier, M. Carre, B. Pourroy, L. Camoin, O. Rebai, C. Briand, et al. Antiangiogenic activity of paclitaxel is associated with its cytostatic effect, mediated by the initiation but not completion of a mitochondrial apoptotic signaling pathway. Mol. Cancer Ther. 3(10):1301–1310 (2004).

    PubMed  CAS  Google Scholar 

  65. H. Schuldes, S. Bade, J. Knobloch, and D. Jonas. Loss of in vitro cytotoxicity of cisplatin after storage as stock solution in cell culture medium at various temperatures. Cancer 79(9):1723–1728 (1997).

    Article  PubMed  CAS  Google Scholar 

  66. I. Ringel, and S. B. Horwitz. Taxol is converted to 7-epitaxol, a biologically-active isomer, in cell-culture medium. J. Pharmacol. Exp. Ther. 242(2):692–698 (1987).

    PubMed  CAS  Google Scholar 

  67. A. Iliadis, and D. Barbolosi. Optimizing drug regimens in cancer chemotherapy by an efficacy-toxicity mathematical model. Comput. Biomed. Res. 33(3):211–226 (2000).

    Article  PubMed  CAS  Google Scholar 

  68. R. B. Martin, M. E. Fisher, R. F. Minchin, and K. L. Teo. A mathematical model of cancer chemotherapy with an optimal selection of parameters. Math. Biosci. 99(2):205–230 (1990).

    Article  PubMed  CAS  Google Scholar 

  69. S. Z. Zhang, K. S. Lovejoy, J. E. Shima, L. L. Lagpacan, Y. Shu, A. Lapuk, et al. Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res. 66(17):8847–8857 (2006).

    Article  PubMed  CAS  Google Scholar 

  70. A. M. Fichtinger-Schepman, F. J. Dijt, P. Bedford, A. T. van Oosterom, B. T. Hill, and F. Berends. Induction and removal of cisplatin-DNA adducts in human cells in vivo and in vitro as measured by immunochemical techniques. IARC Sci. Publ. 89:321–328 (1988).

    PubMed  Google Scholar 

  71. B. Koberle, K. A. Grimaldi, A. Sunters, J. A. Hartley, L. R. Kelland, and J. R. W. Masters. DNA repair capacity and cisplatin sensitivity of human testis tumour cells. Int. J. Cancer 70(5):551–555 (1997).

    Article  PubMed  CAS  Google Scholar 

  72. G. Samimi, and S. B. Howell. Modulation of the cellular pharmacology of JM118, the major metabolite of satraplatin, by copper influx and efflux transporters. Cancer Chemother. Pharmacol. 57(6):781–788 (2006).

    Article  PubMed  CAS  Google Scholar 

  73. P. J. Sadler, and Z. J. Guo. Metal complexes in medicine: design and mechanism of action. Pure Appl. Chem. 70(4):863–871 (1998).

    Article  CAS  Google Scholar 

  74. G. G. Steel, and M. J. Peckham. Exploitable mechanisms in combined radiotherapy-chemotherapy - concept of additivity. Int. J. Radiat. Oncol. Biol. Phys. 5(1):85–91 (1979).

    PubMed  CAS  Google Scholar 

  75. S. Loewe. The problem of synergism and antagonism of combined drugs. Arzneimittelforschung 3(6):285–290 (1953).

    PubMed  CAS  Google Scholar 

  76. D. J. Adams, P. J. Watkins, V. C. Knick, R. L. Tuttle, and K. W. Bair. Evaluation of arylmethylaminopropanediols by a novel in vitro pharmacodynamic assay: correlation with antitumor activity in vivo. Cancer Res. 50(12):3663–3669 (1990).

    PubMed  CAS  Google Scholar 

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Acknowledgement

We thank Saadia Hassan for sending us digitized dose-response data for paclitaxel corresponding to the published figures in Hassan et al. (36). This work was supported by NIH grants CA098671 and CA040355.

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Authors and Affiliations

  1. ARL—Microcirculation Division, University of Arizona, P.O. Box 245051, Tucson, AZ, 85724-5051, USA

    Ardith W. El-Kareh

  2. Program in Applied Mathematics, University of Arizona, Tucson, AZ, USA

    Rachel E. Labes

  3. Department of Physiology, University of Arizona, Tucson, AZ, USA

    Timothy W. Secomb

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  1. Ardith W. El-Kareh
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El-Kareh, A.W., Labes, R.E. & Secomb, T.W. Cell Cycle Checkpoint Models for Cellular Pharmacology of Paclitaxel and Platinum Drugs. AAPS J 10, 15–34 (2008). https://doi.org/10.1208/s12248-007-9003-6

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