Antitumor activity of combretastatin-A4 phosphate, a natural product tubulin inhibitor

Robert T Dorr, Katerina Dvorakova, Kristi Snead, David S Alberts, Sydney E. Salmon, G. Robert Pettit

Research output: Contribution to journalArticle

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Abstract

The tubulin-binding natural product combretastatin A-4 (CA-4) was tested for antitumor activity against fresh human tumors in vitro and 2 mouse tumors, both in vitro and in vivo. In colony forming assays using 10% fetal bovine serum, CA-4 was inhibitory in 27/40 human ovary cancers with a mean IC50 of 3.18 μg/mL for a 1-hour exposure (n = 35 specimens) and 0.27 μg/mL for a continuous exposure to CA-4 for 11-14 days (n = 5 specimens). Murine B-16 melanoma and P-388 leukemia were also highly sensitive to CA-4 in vitro with an identical IC50 value of 0.0007 μg/mL for continuous drug exposure for 8 days. Comparable in vitro cell culture studies performed in serum concentrations higher than 10%, revealed a significant loss of cytotoxic potency. Using the same reversed-phase HPLC technique as developed for paclitaxel, CA-4 was shown to bind to serum proteins (≤ 30,000 mw) > 99% and to albumin approximately 70%. CA-4 was only marginally active (25% increased lifespan) in DBA/2 mice bearing P-388 leukemia who were given doses of 100 mg/kg IP on either days, 1, 5 and 9 (p = 0.075 by Wilcoxon analysis) or on consecutive days 1-9 (p = 0.19 compared to control). A higher IP dose of 150 mg/kg on days 1, 5 and 9 did not delay subcutaneous B-16 melanoma tumor growth in C57/B1 mice. These findings demonstrate a substantial loss of antitumor efficacy for CA-4 in physiologic serum concentrations in vitro. No consistent antitumor activity was observed in two murine tumor models in vivo.

Original languageEnglish (US)
Pages (from-to)131-137
Number of pages7
JournalInvestigational New Drugs
Volume14
Issue number2
StatePublished - 1996

Fingerprint

Tubulin Modulators
Biological Products
Inhibitory Concentration 50
Melanoma
Neoplasms
Leukemia
Serum
Inbred DBA Mouse
Tubulin
Paclitaxel
fosbretabulin
Ovarian Neoplasms
Blood Proteins
Albumins
Cell Culture Techniques
High Pressure Liquid Chromatography
In Vitro Techniques

Keywords

  • Antitumor agent
  • Combretastatin
  • Microtubule inhibition
  • Protein binding

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Antitumor activity of combretastatin-A4 phosphate, a natural product tubulin inhibitor. / Dorr, Robert T; Dvorakova, Katerina; Snead, Kristi; Alberts, David S; Salmon, Sydney E.; Pettit, G. Robert.

In: Investigational New Drugs, Vol. 14, No. 2, 1996, p. 131-137.

Research output: Contribution to journalArticle

Dorr, RT, Dvorakova, K, Snead, K, Alberts, DS, Salmon, SE & Pettit, GR 1996, 'Antitumor activity of combretastatin-A4 phosphate, a natural product tubulin inhibitor', Investigational New Drugs, vol. 14, no. 2, pp. 131-137.
Dorr, Robert T ; Dvorakova, Katerina ; Snead, Kristi ; Alberts, David S ; Salmon, Sydney E. ; Pettit, G. Robert. / Antitumor activity of combretastatin-A4 phosphate, a natural product tubulin inhibitor. In: Investigational New Drugs. 1996 ; Vol. 14, No. 2. pp. 131-137.
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