Summary
Cancer has been the leading cause of death in Taiwan over the past two decades and liver cancer is the leading cause of all cancer deaths in Taiwan with a trend of increase in incidence. Therapeutic options and efficacy for liver cancer have been limited and the 5-year survival rate is less than 7% in the Unite States. The study was conducted to establish a histoculture system of human hepatocellular carcinomas (HCC) for biological and pharmacological studies and to determine the efficacy of anticancer drugs with the established HCC histocultures. Patient HCC tissues freshly obtained after surgeries were prepared and histocultured. The histocultured HCC were treated with doxorubicin and paclitaxel of various concentrations for 96-h. Upon drug treatments, the activity of tumor cell proliferation and extent of cell death induction were measured and changes of the α-fetoprotein levels in the culture medium were determined. We demonstrated that human HCC can be successfully cultured in a 3-dimensional histoculture system and used for pharmacological studies. Doxorubicin and paclitaxel showed concentration-dependent activities in anti-proliferation and cell death induction against the human HCC. Inhibitory effects of both drugs on α-fetoprotein production of the cultured HCC were in agreement with their anti-proliferative effects. Exposure time-dependent antitumoral effects of paclitaxel treatments at 3-, 24-, and 96-h against the histocultured HCC PLC/PRF/5 xenograft tumors were also observed. In conclusion, we have demonstrated a histoculture system for patient HCC and it can be utilized in selection of active drugs prior to treatments in patients and in evaluation of new agents against HCC, for which therapeutic agents are in desperate needs worldwide.
Similar content being viewed by others
References
Montalto G., Cervello M., Giannitrapani L., Dantona F., Terranova A., Castagnetta L.A.,Epidemiology, risk factors, natural history of hepatocellular carcinoma. Ann. N. Y. Acad. Sci. 963:13–20 (2002)
El-Serag H.B.,Hepatocellular carcinoma: an epidemiologic view. J. Clin. Gastroenterol. 35(5 Suppl 2):S72–78 (2002)
Llovet J.M., Burroughs A., Bruix J., Hepatocellular carcinoma. Lancet 362:1907–1917 (2003)
Bosch F.X., Ribes J., Diaz M., Cleries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology 127(5 Suppl 1):S5-S16. (2004)
Lee Y.T., Primary carcinoma of the liver: diagnosis, prognosis, and management. J. Surg. Oncol. 22:17–25 (1983)
Jemal A., Siegel R., Ward E., Murray T., Xu J., Smigal C., Thun M.J., Cancer statistics, 2006. CA. Cancer J. Clin. 56:106–130 (2006)
Chang M.H., Chen C.J., Lai M.S., Hsu H.M., Wu T.C., Kong M.S., Liang D.C., Shau W.Y., Chen D.S., Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N. Engl. J. Med. 336:1855–1859 (1997)
Liaw Y.F., Sung J.J., Chow W.C., Farrell G., Lee C.Z., Yuen H., Tanwandee T., Tao Q.M., Shue K., Keene O.N., Dixon J.S., Gray D.F., Sabbat J.; Cirrhosis Asian Lamivudine Multicentre Study Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease N. Engl. J. Med. 351:1521–1531 (2004)
Lee C.L., Ko Y.C., Choong C.S., Survival rate for liver cancer in Taiwan. Zhonghua Yi Xue Za Zhi (Taipei) 63:16–20 (2000)
Mor E., Kaspa R.T., Sheiner P., Schwartz M., Treatment of hepatocellular carcinoma associated with cirrhosis in the era of liver transplantation. Ann. Intern. Med. 129: 643–653 (1998)
Nagorney D.M., van Heerden J.A., Ilstrup D.M., Adson M.A.. Primary hepatic malignancy: surgical management and determinants of survival. Surgery 106:740–749, (1989)
Tsuzuki T., Sugioka A., Ueda M., Iida S., Kanai T., Yoshii H., Nakayasu K., Hepatic resection for hepatocellular carcinoma. Surgery 107:511–520, (1990)
Whang-Peng J., Chao Y., Clinical trials of HCC in Taiwan. Hepatogastroenterology 45:1937–1943, (1998)
Furukawa T., Kubota T., Hoffman RM, Clinical applications of the histoculture drug response assay. Clin. Cancer Res. 1:305–311 (1995)
Robbins K.T., Connors K.M., Storniolo AM., Hanchett C, Hoffman R.M., Sponge-gel-supported histoculture drug-response assay for head and neck cancer. Correlations with clinical response to cisplatin. Arch. Otolaryngol. Head Neck Surg. 120:288–292 (1994)
Tanino H., Oura S., Hoffman R.M., Kubota T., Furukawa T., Arimoto J., Yoshimasu T., Hirai I., Bessho T., Suzuma T., Sakurai T., Naito Y., Acquisition of multidrug resistance in recurrent breast cancer demonstrated by the histoculture drug response assay. Anticancer Res. 21:4083–4086 (2001)
Chen C.T., Gan Y., Au J.L., Wientjes M.G., Androgen-dependent and – independent human prostate xenograft tumors as models for drug activity evaluation. Cancer Res. 58: 2777–2783, (1998)
Gan Y., Wientjes M.G., Badalament R.A., Au J.L., Pharmacodynamics of doxorubicin in human bladder tumors. Clin. Cancer Res. 2:1275–1283 (1996)
Tangkijvanich P., Anukulkarnkusol N., Suwangool P., Lertmaharit S., Hanvivatvong O., Kullavanijaya P., Poovorawan Y., (2000) Clinical characteristics and prognosis of hepatocellular carcinoma: analysis based on serum alpha-fetoprotein levels. J. Clin. Gastroenterol. 31:302–308
Soresi M., Magliarisi C., Campagna P., Leto G., Bonfissuto G., Riili A., Carroccio A, Sesti R, Tripi S, Montalto G (2003) Usefulness of alpha-fetoprotein in the diagnosis of hepatocellular carcinoma. Anticancer Res. 23:1747–1753
Ohie S., Udagawa Y., Kozu A., Komuro Y., Aoki D., Nozawa S., Moossa A.R., Hoffman R.M. (2000) Cisplatin sensitivity of ovarian cancer in the histoculture drug response assay correlates to clinical response to combination chemotherapy with cisplatin, doxorubicin and cyclophosphamide. Anticancer Res. 20:2049–2054
Hoffman R.M., (2000) The clinical benefit of the histoculture drug response assay. Jpn. J. Cancer Chemotherapy 27(Suppl 2):321–322
Hoffman R.M., (1991) Three-dimensional histoculture: origins and applications in cancer research. Cancer Cell 3:86–92
Boess F., Kamber M., Romer S., Gasser R., Muller D., Albertini S., Suter L. (2003) Gene expression in two hepatic cell lines, cultured primary hepatocytes, and liver slices compared to the in vivo liver gene expression in rats: possible implications for toxicogenomics use of in vitro systems. Toxicol. Sci. 73:386–402
Jaeschke H.. (2003) Are cultured liver cells the right tool to investigate mechanisms of liver disease or hepatotoxicity? Hepatology 38:1053–1055
Ariyoshi Y., Shimahara M., Tanigawa N.. (2003) Study on chemosensitivity of oral squamous cell carcinomas by histoculture drug response assay. Oral Oncol. 39:701–707
Hirano Y., Kageyama S., Ushiyama T., Suzuki K., Fujita K.. (2001) Clinical usefulness of chemotherapy based on an in vitro chemosensitivity test in urothelial cancer patients. Anticancer Res. 21:4061–4066
Speth P.A., Linssen P.C., Holdrinet R.S., Haanen C.. 1987 Plasma and cellular adriamycin concentrations in patients with myeloma treated with ninety-six-hour continuous infusion. Clin. Pharmacol. Ther. 41:661–665
Bugat R., Robert J., Herrera A., Pinel M.C., Huet S., Chevreau C., Boussin G., Roquain J., Carton M.. (1989) Clinical pharmacokinetic study of 96-h infusions of doxorubicin in advanced cancer patients. Eur. J. Cancer Clin. Oncol. 25:505–511
Adams D.J., In vitro pharmacodynamic assay for cancer drug development: application to crisnatol, a novel DNA intercalator. Cancer Res. 49:6615–6620 (1989)
Olweny C.L., Toya T., Katongole-Mbidde E., Mugerwa J., Kyalwazi S.K., Cohen H., Treatment of hepatocellular carcinoma with adriamycin. Cancer 36:1250–1257 (1975)
Doci R., Bignami P., Bozzetti F., Bonfanti G., Audisio R., Colombo M., Gennari L., Intrahepatic chemotherapy for unresectable hepatocellular carcinoma. Cancer 61:1983–1987 (1988)
Barone M., Ettorre G.C., Ladisa R., Schiavariello M., Santoro C., Francioso G., Vinciguerra V., Francavilla A., Transcatheter arterial chemoembolization (TACE) in treatment of hepatocellular carcinoma. Hepatogastroenterology 50:183–187 (2003)
Raoul J.L., Heresbach D., Bretagne J.F., Bentue Ferrer D., Duvauferrier R., Bourguet P., Messner M. and Gosselin M., Chemoembolization of hepatocellular carcinomas. A study of the biodistribution and pharmacokinetics of doxorubicin. Cancer 70: 585–590, 1992
Lai C.L., Wu P.C., Chan G.C., Lok A.S., Lin H.J., Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma. A prospective randomized trial. Cancer 62:479–483 (1988)
Cheng J.C., Chuang V.P., Cheng S.H., Huang A.T., Lin Y.M., Cheng T.I., Yang P.S., You D.L., Jian J.J., Tsai S.Y., Sung J.L., Horng C.F., Local radiotherapy with or without transcatheter arterial chemoembolization for patients with unresectable hepatocellular carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 47:435–442 (2000)
Wilson W.H., Berg S.L., Bryant G., Wittes R.E., Bates S., Fojo A., Steinberg S.M., Goldspiel B.R., Herdt J., O’Shaughnessy J., et al Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: a phase I/II trial of 96-hour infusion. J. Clin. Oncol. 12:1621–1629 (1994)
Gligorov J, Lotz JP.. Preclinical pharmacology of the taxanes: implications of the differences. Oncologist 9(Suppl 2):3–8 (2004)
Strumberg D., Erhard J., Harstrick A., Klaassen U., Muller C., Eberhardt W., Wilke H., Seeber S., Phase I study of a weekly 1 h infusion of paclitaxel in patients with unresectable hepatocellular carcinoma. Eur. J. Cancer 34:1290–1292 (1998)
Panday V.R.N., ten Bokkel Huinink W.W., Vermorken J.B., Rosing H., Koopman F.J., Swart M., Schellens J.H., Beijnen J.H., Pharmacokinetics of paclitaxel administered as a 3-hour or 96-hour infusion. Pharmacol. Res. 40:67–74 (2004)
Seidman A.D., Hochhauser D., Gollub M., Edelman B., Yao T.J., Hudis C.A., Francis P., Fennelly D., Gilewski T.A., Moynahan M.E., Currie V., Baselga J., Tong W., O’Donaghue M., Salvaggio R., Auguste L., Spriggs D., Norton L., Ninety-six-hour paclitaxel infusion after progression during short taxane exposure: a phase II pharmacokinetic and pharmacodynamic study in metastatic breast cancer. J. Clin. Oncol. 14:1877–1884 (1996)
Minemura M., Tanimura H., Tabor E., Overexpression of multidrug resistance genes MDR1 and cMOAT in human hepatocellular carcinoma and hepatoblastoma cell lines. Int. J. Oncol. 15:559–563 (1999)
Nies A.T., Konig J., Pfannschmidt M., Klar E., Hofmann W.J., Keppler D., Expression of the multidrug resistance proteins MRP2 and MRP3 in human hepatocellular carcinoma. Int. J. Cancer 94:492–499 (2001)
Chao Y., Chan W.K., Birkhofer M.J., Hu O.Y, Wang S.S., Huang Y.S., Liu M, Whang-Peng J., Chi K.H., Lui W.Y., Lee S.D.. Phase II and pharmacokinetic study of paclitaxel therapy for unresectable hepatocellular carcinoma patients. Br. J. Cancer 78:34–39 (1998)
Fuchs J., Habild G., Leuschner I., Schweinitz D.V., Haindl J., Knon E., Paclitaxel: an effective antineoplastic agent in the treatment of xenotransplanted hepatoblastoma. Med. Pediatr. Oncol. 32:209–215 (1999)
Chang A.Y., Boros L., Garrow G., Asbury R.. (1995) Paclitaxel by 3-hour infusion followed by 96-hour infusion on failure in patients with refractory malignant disease. Semin. Oncol. 22(3 Suppl 6):124–127 (1995)
Younes A., Ayoub J.P., Hagemeister F.B., McLaughlin P., Sarris A., Rodriguez M.A., Swan F. Jr., Romaguera J.E., Martin J., Cabanillas F., No effect of 96-hour paclitaxel infusion in patients with relapsed non-Hodgkin’s lymphoma refractory to a 3-hour infusion schedule. J. Clin. Oncol. 14:543–548 (1996)
Markman M., Rose P.G., Jones E., Horowitz I.R., Kennedy A., Webster K., Belinson J., Fusco N., Fluellen L., Kulp B., Peterson G., McGuire W.P., Ninety-six hour infusional paclitaxel as salvage therapy of ovarian cancer patients previously failing treatment with 3-hour or 24-hour paclitaxel infusion regimens. J. Clin. Oncol. 16:1849–1851 (1998)
Lopez R.R. Jr., Pan S.H., Lois J.F., McMonigle M.E., Hoffman A.L., Sher L.S., Lugo D., Makowka L.,.Transarterial chemoembolization is a safe treatment for unresectable hepatic malignancies. Ann. Surg. 63:923–926 (1997)
Yoon C.J., Chung J.W., Park J.H., Yoon Y.H., Lee J.W., Jeong S.Y., Chung H.,. Transcatheter arterial chemoembolization with paclitaxel-lipiodol solution in rabbit VX2 liver tumor. Radiology 229:126–131 (2003)
Acknowledgements
This study was supported by grants BP-091-CF03, BP-092-PP-10, and BP-093-PP-11 of The National Health Research Institutes and NSC 92-2218-E-400-001 from National Science Council, Taiwan, R.O.C. We would like to thank Dr. Y. S. Chao, Dr. C. M. Chang, Ms. H. W. Chu and Ashley Chen for their administrative supports and Mung-Pei Tsai for technical assistance.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Chuu, JJ., Liu, J.M., Tsou, MH. et al. Effects of paclitaxel and doxorubicin in histocultures of hepatocelular carcinomas. J Biomed Sci 14, 233–244 (2007). https://doi.org/10.1007/s11373-006-9141-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11373-006-9141-3