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Chemosensitization and radiosensitization of human lung and colon cancers by antimitotic agent, ABT-751, in athymic murine xenograft models of subcutaneous tumor growth.

AbstractPURPOSE:
ABT-751 is an orally active antimitotic agent that is currently in Phase II clinical trials. This agent binds to the colchicine site on ss-tubulin and inhibits polymerization of microtubules. This disruption of microtubule dynamics leads to a block in the cell cycle at the G2/M phase, and promotes apoptosis. ABT-751, as a single agent, has antitumor activity against a series of xenograft models including non-small cell lung cancer (NSCLC) and colon cancer. The current studies were conducted to determine whether ABT-751 enhances antitumor activity of standard cytotoxic therapies currently in clinical use.
METHODS:
Efficacy of ABT-751, in combination with cisplatin, 5-FU, and radiation, was evaluated in the Calu-6 NSCLC, HT-29 colon, and HCT-116 colon carcinoma xenograft models, respectively. Tumor-bearing athymic mice were treated with ABT-751 orally once a day at 75 or 100 mg/kg/day on a 5-days-on, 5-days-off schedule for two cycles.
RESULTS:
Efficacy of ABT-751 at 100 mg/kg/day was tested in combination with cisplatin at its maximum tolerable dose (MTD) (10 mg/kg/day, i.p. x1) in Calu-6 tumor-bearing athymic mice. The percent treated/control (%T/C) tumor volume ratios on day 38 were 35, 37, and 6, and the percent tumor growth delay (%TGD) values were 71, 65, and 188 for cisplatin, ABT-751 and the combination groups, respectively. HT-29 colon tumors were used to test ABT-751 in combination with an MTD of 5-FU, 30 mg/kg/day, i.p., q.d. x5. The %T/C ratios on day 38 were 22, 28, and 5 and the %TGD values were 75, 75, and 150 for 5-FU, ABT-751, and the combination groups, respectively. Treatment of HCT-116 colon carcinoma tumors with ABT-751, concurrent with the radiation treatment, was able to both enhance radiation-induced tumor regression, and delay the time to recurrence and progression. Growth curves allowed calculation of enhancement of radiation-induced growth delay (defined as the additional time required for a treated tumor to reach four times its original size) of 2, 9, and 12 days, for ABT-751 alone, radiation alone, and the combination, respectively.
CONCLUSION:
Collectively, these studies demonstrate that ABT-751 enhanced efficacy of standard cytotoxic therapies in a variety of tumor xenograft models, and that enhancement was at least additive in all systems.
AuthorsTimothy J Jorgensen, Hui Tian, Ingrid B J K Joseph, Krishna Menon, David Frost
JournalCancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 59 Issue 6 Pg. 725-32 (May 2007) ISSN: 0344-5704 [Print] Germany
PMID16967299 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • ABT751
  • Antimitotic Agents
  • Radiation-Sensitizing Agents
  • Sulfonamides
  • Cisplatin
  • Fluorouracil
Topics
  • Animals
  • Antimitotic Agents (pharmacology)
  • Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
  • Cisplatin (administration & dosage)
  • Colonic Neoplasms (drug therapy)
  • Drug Evaluation, Preclinical (methods)
  • Drug Synergism
  • Fluorouracil (administration & dosage)
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Lung Neoplasms (drug therapy)
  • Mice
  • Mice, Nude
  • Radiation-Sensitizing Agents (pharmacology)
  • Sulfonamides (pharmacology, therapeutic use)
  • Time Factors
  • Xenograft Model Antitumor Assays

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