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The activity of camptothecin analogues is enhanced in histocultures of human tumors and human tumor xenografts by modulation of extracellular pH.

Publication ,  Journal Article
Flowers, JL; Hoffman, RM; Driscoll, TA; Wall, ME; Wani, MC; Manikumar, G; Friedman, HS; Dewhirst, M; Colvin, OM; Adams, DJ
Published in: Cancer Chemother Pharmacol
September 2003

BACKGROUND: Most solid human tumors exist in an acidic microenvironment, due in part to inefficient vasculature and a higher intrinsic rate of glycolysis. This leads to a tumor-selective pH gradient, which can be exploited therapeutically with antitumor agents such as the camptothecins (CPTs). Previous work in this laboratory has shown that camptothecin activity is enhanced 40- to 60-fold in monolayer cell culture by reducing the extracellular pH to 6.8. Three-dimensional histoculture has been shown to be a technique that allows human tumor tissue to grow in an in vivo-like way with maintenance of tissue histology and function and drug sensitivity for long periods of time. PURPOSE: In the current study, we utilized these features of histoculture to study new analogues of camptothecin that have superior pharmacological properties. METHODS: We evaluated six CPT analogues in histocultures of human brain, neuroblastoma, breast, colon, and prostate tumors. Fragments were exposed to 10,11-methylenedioxy-CPT (MDC), 7-chloromethyl-MDC, SN-38, topotecan (TPT), 9-amino-CPT, 10-amino-CPT, paclitaxel, 5-fluorouracil, 4-hydroperoxycyclophosphamide and doxorubicin, and antitumor activity was assessed. For in vivo tumor outgrowth studies, fragments were treated in parallel, implanted into nude mice, and monitored for development of tumors. RESULTS. Against 15 of 16 tumor xenografts and all primary tumor samples tested, all compounds were cytotoxic at pH 7.4 (IC(50) range 13-921 microM). MDC, SN-38, TPT, and 9-amino-CPT achieved an average 5-fold increase in activity (range 3-14) at pH 6.8, while 7-chloromethyl-MDC was enhanced 8-fold (range 6-14). The most potentiated analogue was 10-amino-CPT at 27-fold (range 17-49). In contrast, the other agents were active against one or more tumor types but were not enhanced by acidic pH. Importantly, the toxicity of MDC in histoculture of D54 glioma xenografts strongly correlated with the outgrowth of treated fragments subsequently implanted in vivo. CONCLUSION: Evaluation of anticancer drug activity in native-state histoculture supports the concept that pH modulation may be an important approach to improve the selectivity and antitumor effectiveness of camptothecin-based chemotherapy.

Duke Scholars

Published In

Cancer Chemother Pharmacol

DOI

ISSN

0344-5704

Publication Date

September 2003

Volume

52

Issue

3

Start / End Page

253 / 261

Location

Germany

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Prostatic Neoplasms
  • Oncology & Carcinogenesis
  • Mice, Inbred BALB C
  • Mice
  • Male
  • Hydrogen-Ion Concentration
  • Humans
  • Female
 

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Flowers, J. L., Hoffman, R. M., Driscoll, T. A., Wall, M. E., Wani, M. C., Manikumar, G., … Adams, D. J. (2003). The activity of camptothecin analogues is enhanced in histocultures of human tumors and human tumor xenografts by modulation of extracellular pH. Cancer Chemother Pharmacol, 52(3), 253–261. https://doi.org/10.1007/s00280-003-0635-7
Flowers, James L., Robert M. Hoffman, Timothy A. Driscoll, Monroe E. Wall, Mansukh C. Wani, Govindarajan Manikumar, Henry S. Friedman, Mark Dewhirst, O Michael Colvin, and David J. Adams. “The activity of camptothecin analogues is enhanced in histocultures of human tumors and human tumor xenografts by modulation of extracellular pH.Cancer Chemother Pharmacol 52, no. 3 (September 2003): 253–61. https://doi.org/10.1007/s00280-003-0635-7.
Flowers JL, Hoffman RM, Driscoll TA, Wall ME, Wani MC, Manikumar G, et al. The activity of camptothecin analogues is enhanced in histocultures of human tumors and human tumor xenografts by modulation of extracellular pH. Cancer Chemother Pharmacol. 2003 Sep;52(3):253–61.
Flowers, James L., et al. “The activity of camptothecin analogues is enhanced in histocultures of human tumors and human tumor xenografts by modulation of extracellular pH.Cancer Chemother Pharmacol, vol. 52, no. 3, Sept. 2003, pp. 253–61. Pubmed, doi:10.1007/s00280-003-0635-7.
Flowers JL, Hoffman RM, Driscoll TA, Wall ME, Wani MC, Manikumar G, Friedman HS, Dewhirst M, Colvin OM, Adams DJ. The activity of camptothecin analogues is enhanced in histocultures of human tumors and human tumor xenografts by modulation of extracellular pH. Cancer Chemother Pharmacol. 2003 Sep;52(3):253–261.
Journal cover image

Published In

Cancer Chemother Pharmacol

DOI

ISSN

0344-5704

Publication Date

September 2003

Volume

52

Issue

3

Start / End Page

253 / 261

Location

Germany

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Prostatic Neoplasms
  • Oncology & Carcinogenesis
  • Mice, Inbred BALB C
  • Mice
  • Male
  • Hydrogen-Ion Concentration
  • Humans
  • Female