Relationship between the cellular accumulation and the cytotoxicity of S12363, a new Vinca alkaloid derivative

Cancer Chemother Pharmacol. 1992;29(5):367-74. doi: 10.1007/BF00686005.


S12363, a new vinca alkaloid derivative, was considerably more cytotoxic to murine L1210 cells and five human tumor cell lines (HL60, HT-29, COLO 320DM, NCI-H460, and PANC-1) than was vincristine (VCR) or vinblastine (VLB). S 12,363 bound to tubulin in crude extracts from brain or L1210 cells with an affinity similar to that of VLB and VCR (apparent Kd value: 1.1-1.6, 1.2-1.7, and 0.6-0.8 microM, respectively). After 1 h exposure, the accumulation of 20 nM [3H]-S 12,363 by L1210 cells was 4- to 18-fold that of [3H]-VLB and [3H]-VCR, respectively. After the cells had been preloaded for 1 h with the labeled drugs and then incubated for 3 h in drug-free medium, 37%-55% of the [3H]-S 12,363 was retained by the cells vs 36%-47% of the [3H]-VCR and less than 6% of the [3H]-VLB. Similar results were obtained for the five human cell lines tested. The accumulation factors (intracellular vs extracellular concentrations) found for [3H]-S 12,363 (54- to 167-fold) were significantly higher than those observed for [3H]-VCR (5- to 14-fold) or [3H]-VLB (19- to 41-fold). Greater than 90% of the radioactivity extracted from L1210 cells that had been treated with [3H]-S 12,363 was recovered as unmodified drug, demonstrating that [3H]-S 12,363 was not metabolized by these cells. S 12,362, which differs from S 12,363 only in the absolute configuration of the asymmetric carbon atom of its alpha-aminophosphonic side chain, was 300 times less cytotoxic, bound to tubulin with a lower affinity (apparent Kd value, 4.9-9.6 microM), and was neither accumulated nor retained by the cells. Taken together, these results demonstrate that the potency of S 12,363 is due at least in part to its cellular accumulation and retention.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / analysis
  • Antineoplastic Agents, Phytogenic / pharmacokinetics*
  • Antineoplastic Agents, Phytogenic / toxicity
  • Binding, Competitive / drug effects
  • Brain / drug effects
  • Brain / metabolism
  • Cell Line
  • Chromatography, High Pressure Liquid
  • Humans
  • Leukemia L1210 / metabolism
  • Protein Binding / drug effects
  • Tritium
  • Tubulin / drug effects
  • Tubulin / metabolism
  • Tumor Cells, Cultured / chemistry
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism
  • Vinblastine / analysis
  • Vinblastine / pharmacokinetics
  • Vinblastine / toxicity
  • Vinca Alkaloids / analysis
  • Vinca Alkaloids / pharmacokinetics*
  • Vinca Alkaloids / toxicity
  • Vincristine / analysis
  • Vincristine / pharmacokinetics
  • Vincristine / toxicity


  • Antineoplastic Agents, Phytogenic
  • Tubulin
  • Vinca Alkaloids
  • Tritium
  • S 12363
  • Vincristine
  • Vinblastine