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Antisense strategies targeting protein kinase C: preclinical and clinical development

Giampaolo Tortora1, Fortunato Ciardiello

  • 1Department of Molecular and Clinical Endocrinology and Oncology, Università di Napoli Federico II, Naples, Italy.

Seminars in Oncology
|August 15, 2003
PubMed

Insights

Antisense oligonucleotide LY900003 selectively inhibits protein kinase C-alpha (PKC-alpha) production. Clinical trials show promising antitumor activity, especially when combined with chemotherapy for non-small cell lung cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Altered protein kinase C-alpha (PKC-alpha) expression is linked to tumor promotion and carcinogenesis.
  • Antisense oligonucleotides offer a targeted approach to inhibit PKC-alpha production.

Purpose of the Study:

  • To evaluate the therapeutic potential of the antisense oligonucleotide LY900003 (ISIS 3521) for cancer treatment.
  • To assess the efficacy of LY900003 as a single agent and in combination with chemotherapy.

Main Methods:

  • Preclinical studies assessed LY900003's inhibition of PKC-alpha mRNA and protein expression and its antitumor activity.
  • Clinical studies (Phase I, II, and III) investigated LY900003's safety and efficacy in various cancer types, particularly non-small cell lung cancer, in combination with chemotherapy regimens.

Main Results:

  • LY900003 demonstrated selective inhibition of PKC-alpha expression and significant antitumor activity in preclinical models.
  • Clinical studies indicated LY900003 has activity as a single agent, with most promising results observed when combined with chemotherapy, especially in non-small cell lung cancer patients.

Conclusions:

  • LY900003 shows therapeutic promise as an inhibitor of PKC-alpha.
  • Combining LY900003 with conventional chemotherapy represents a promising strategy for treating non-small cell lung cancer and potentially other tumor types.

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