Skip to main content
NCBI home page
AAPS PharmSci logoLink to AAPS PharmSci
. 2001 May 15;3(2):69–77. doi: 10.1208/ps030215

Time-and concentration-dependent penetration of doxorubicin in prostate tumors

Jenny H Zheng 1,2, Chiung-Tong Chen 1,2, Jessie L S Au 1,2, M Guill Wientjes 1,2,✉
PMCID: PMC2779556  PMID: 11741266

Abstract

The penetration of paclitaxel into multilayered solid tumors is time- and concentration-dependent, a result of the drug-induced apoptosis and changes in tissue composition. This study evaluates whether this tissue penetration property applies to other highly protein-bound drugs capable of inducing apoptosis. The penetration of doxorubicin was studied in histocultures of prostate xenograft tumors and tumor specimens obtained from patients who underwent radical prostatectomy. The kinetics of drug uptake and efflux in whole tumor histocultures were studied by analyzing the average tumor drug concentration using high-pressure liquid chromatography. Spatial drug distribution in tumors and the drug concentration gradient across the tumors were studied using fluorescence microscopy. The results indicate that drug penetration was limited to the periphery for 12 hours in patient tumors and to 24 hours in the more densely packed xenograft tumors. Subsequently, the rate of drug penetration to the deeper tumor tissue increased abruptly in tumors treated with higher drug concentrations capable of inducing apoptosis (i.e., >5 μm), but not in tumors treated with lower concentrations. These findings indicate a time- and concentration-dependent penetration of doxorubicin in solid tumors, similar to that of paclitaxel. We conclude that doxorubicin penetration in solid tumors is time- and concentration-dependent and is enhanced by drug-induced cell death.

Key words: Doxorubicin, Delivery, Apoptosis, Solid Tumor

References

  • 1.Jain RK. Barriers to drug delivery in solid tumors. Sci Am. 1994;271:58–65. doi: 10.1038/scientificamerican0794-58. [DOI] [PubMed] [Google Scholar]
  • 2.Nativ O, Aronson M, Medalia O, et al. Anti-neoplastic activity of paclitaxel on experimental superficial bladder cancer: in vivo and in vitro studies. Int J Cancer. 1997;70:297–301. doi: 10.1002/(SICI)1097-0215(19970127)70:3<297::AID-IJC9>3.0.CO;2-S. [DOI] [PubMed] [Google Scholar]
  • 3.Song D, Wientjes M G, Au J L-S. Bladder tissue pharmacokinetics of intravesical taxol. Cancer Chemother Pharmacol. 1997;40:285–292. doi: 10.1007/s002800050660. [DOI] [PubMed] [Google Scholar]
  • 4.Song D, Wientjes MG, Gan Y, Au JL-S. Bladder tissue pharmacokinetics and antitumor effect of intravesical 5-fluorouridine. Clin Cancer Res. 1997;3:901–909. [PubMed] [Google Scholar]
  • 5.Markman M, Francis P, Rowinsky E, Hoskins W. Intrapentoneal paclitaxel: a possible role in the management of ovarian cancer? Semin Oncol. 1995;22:84–87. [PubMed] [Google Scholar]
  • 6.Markman M. Intraperitoneal therapy of ovarian cancer. Semin Oncol. 1998;25:356–360. [PubMed] [Google Scholar]
  • 7.Kerr DJ, Kaye SB. Aspects of cytotoxic drug penetration, with particular reference to anthracyclines. Cancer Chemother Pharmacol. 1987;19:1–5. doi: 10.1007/BF00296245. [DOI] [PubMed] [Google Scholar]
  • 8.Durand RE. Slow penetration of anthracyclines into spheroids and tumors: a therapeutic advantage? Cancer Chemother Pharmacol. 1992;26:198–204. doi: 10.1007/BF02897199. [DOI] [PubMed] [Google Scholar]
  • 9.Erlanson M, Daniel-Szolgay E, Carlsson J. Relations between the penetration, binding and average concentration of cytostatic drugs in human tumour spheroids. Cancer Chemother Pharmacol. 1992;29:343–353. doi: 10.1007/BF00686002. [DOI] [PubMed] [Google Scholar]
  • 10.Baguley BC, Finlay GJ. Pharmacokinetic/cytokinetic principles in the chemotherapy of solid tumours. Clin Exp Pharmacol Physiol. 1995;22:825–828. doi: 10.1111/j.1440-1681.1995.tb01943.x. [DOI] [PubMed] [Google Scholar]
  • 11.Tunggal JK, Cowan DS, Shaikh H, Tannock IF. Penetration of anticancer drugs through solid tissue: a factor that limits the effectiveness of chemotherapy for solid tumors. Clin Cancer Res. 1999;5:1583–1586. [PubMed] [Google Scholar]
  • 12.Durand RE. Distribution and activity of antineoplastic drugs in a tumor model. J Natl Cancer Inst. 1989;81:146–152. doi: 10.1093/jnci/81.2.146. [DOI] [PubMed] [Google Scholar]
  • 13.Lankelma J, Dekker H, Luque FR, et al. Doxorubicin gradients in human breast cancer. Clin Cancer Res. 1999;5:1703–1707. [PubMed] [Google Scholar]
  • 14.Kuh HJ, Jang SH, Wientjes MG, Weaver JR, Au JL-S. Determinants of paclitaxel penetration and accumulation in human solid tumor. J Pharmacol Exp Ther. 1999;290:871–880. [PubMed] [Google Scholar]
  • 15.Hamilton G. Multicellular spheroids as an in vitro tumor model. Cancer Lett. 1998;131:29–34. doi: 10.1016/S0304-3835(98)00198-0. [DOI] [PubMed] [Google Scholar]
  • 16.Kunz-Schughart LA. Multicellular tumor spheroids: intermediates between monolayer culture and in vivo tumor. Cell Biol Int. 1999;23:157–161. doi: 10.1006/cbir.1999.0384. [DOI] [PubMed] [Google Scholar]
  • 17.Kabalin JN, Peehl DM, Stamey TA. Clonal growth of human prostatic epithelial cells is stimulated by fibroblasts. Prostate. 1989;14:251–263. doi: 10.1002/pros.2990140306. [DOI] [PubMed] [Google Scholar]
  • 18.Robbins KT, Connors KM, Storniolo AM, Hanchett C, Hoffman RM. Sponge-gel-supported histoculture drug-response assay for head and neck cancer Correlations with clinical response to cisplatin. Arch Otolaryngol Head Neck Surg. 1994;120:288–292. doi: 10.1001/archotol.1994.01880270036007. [DOI] [PubMed] [Google Scholar]
  • 19.Furukawa T, Kubota T, Hoffman RM. Clinical applications of the histoculture drug response assay. Clin Cancer Res. 1995;1:305–311. [PubMed] [Google Scholar]
  • 20.Kubota T, Sasano N, Abe O, et al. Potential of the histoculture drug-response assay to contribute to cancer patient survival. Clin Cancer Res. 1995;1:1537–1543. [PubMed] [Google Scholar]
  • 21.Pretlow TG, Wolman SR, Micale MA, et al. Xenografts of primary human prostatic carcinoma. J Natl Cancer Inst. 1993;85:394–398. doi: 10.1093/jnci/85.5.394. [DOI] [PubMed] [Google Scholar]
  • 22.Nagabhushan M, Miller CM, Pretlow TP, et al. CWR22: the first human prostate cancer xenograft with strongly androgen-dependent and relapsed strains both in vivo and in soft agar. Cancer Res. 1996;56:3042–3046. [PubMed] [Google Scholar]
  • 23.Chen CT, Au JL-S, Wientjes MG. Pharmacodynamics of doxorubicin in human prostate tumors. Clin Cancer Res. 1998;4:277–282. [PubMed] [Google Scholar]
  • 24.Chai M, Wientjes MG, Badalament RA, Burgers JK, Au JL-S. Pharmacokinetics of intravesical doxorubicin in superficial bladder cancer patients. J Urol. 1994;152:374–378. doi: 10.1016/s0022-5347(17)32742-8. [DOI] [PubMed] [Google Scholar]
  • 25.Cox SK, Wilke AV, Frazier D. Determination of adriamycin in plasma and tissue biopsies. J Chromatogr. 1991;564:322–329. doi: 10.1016/0378-4347(91)80098-W. [DOI] [PubMed] [Google Scholar]
  • 26.Schultz JS, Armstrong W. Permeability of interstitial space of muscle (rat diaphragm) to solutes of different molecular weights. J Pharm Sci. 1978;67:696–705. doi: 10.1002/jps.2600670534. [DOI] [PubMed] [Google Scholar]
  • 27.Fox JR, Wayland H. Interstitial diffusion of macromolecules in the rat mesentery. Microvasc Res. 1979;18:255–276. doi: 10.1016/0026-2862(79)90033-5. [DOI] [PubMed] [Google Scholar]
  • 28.Stohrer M, Boucher Y, Stangassinger M, Jain RK. Oncotic pressure in solid tumor is elevated. Cancer Res. 2000;60:4251–4255. [PubMed] [Google Scholar]
  • 29.Kaye SB. Multidrug resistance: clinical relevance in solid tumours and strategies for circumvention. Curr Opin Oncol. 1998;1:S15–S19. [PubMed] [Google Scholar]
  • 30.Chen CT, Au JL-S, Wientjes MG. Androgen-dependent and-independent human prostate xenograft tumors as models for drug development. Cancer Res. 1998;58:2777–2783. [PubMed] [Google Scholar]
  • 31.Brussel JP, Steenbrugge GJ, Romijn JC, Schroder FH, Mickisch GH. Chemosensitivity of prostate cancer cell lines and expression of multidrug resistance-related proteins. Eur J Cancer. 1999;35:664–671. doi: 10.1016/S0959-8049(98)00435-3. [DOI] [PubMed] [Google Scholar]
  • 32.Jang S-H, Wientjes MG, Au JL-S. Enhancement of paclitaxel delivery to solid tumors by apoptosis-inducing pretreatment effect of treatment schedule. J Pharmacol Exper Therap. 2001; in press. [PubMed]
  • 33.Legha SS, Benjamin RS, Mackay B, et al. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med. 1982;96:133–139. doi: 10.7326/0003-4819-96-2-133. [DOI] [PubMed] [Google Scholar]
  • 34.Speth PAJ, Linssen PCM, Holdrinet RSG, Haanen C. Plasma and cellular adriamycin concentrations in patients with myeloma treated with ninety-six-hour continuous infusion. Clin Pharmacol Ther. 1987;41:661–665. doi: 10.1038/clpt.1987.92. [DOI] [PubMed] [Google Scholar]
  • 35.Bugat R, Robert J, Herrera A, et al. Clinical and pharmacokinetic study of 96-h infusions of doxorubicin in advanced cancer patients. Eur J Cancer Clin Oncol. 1989;25:505–511. doi: 10.1016/0277-5379(89)90264-2. [DOI] [PubMed] [Google Scholar]

Articles from AAPS PharmSci are provided here courtesy of American Association of Pharmaceutical Scientists

RESOURCES