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Safety and antitumor activity of recombinant soluble Apo2 ligand
1Department of Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080-4990, USA.
Abstract:
TNF and Fas ligand induce apoptosis in tumor cells; however, their severe toxicity toward normal tissues hampers their application to cancer therapy. Apo2 ligand (Apo2L, or TRAIL) is a related molecule that triggers tumor cell apoptosis. Apo2L mRNA is expressed in many tissues, suggesting that the ligand may be nontoxic to normal cells. To investigate Apo2L's therapeutic potential, we generated in bacteria a potently active soluble version of the native human protein. Several normal cell types were resistant in vitro to apoptosis induction by Apo2L. Repeated intravenous injections of Apo2L in nonhuman primates did not cause detectable toxicity to tissues and organs examined. Apo2L exerted cytostatic or cytotoxic effects in vitro on 32 of 39 cell lines from colon, lung, breast, kidney, brain, and skin cancer. Treatment of athymic mice with Apo2L shortly after tumor xenograft injection markedly reduced tumor incidence. Apo2L treatment of mice bearing solid tumors induced tumor cell apoptosis, suppressed tumor progression, and improved survival. Apo2L cooperated synergistically with the chemotherapeutic drugs 5-fluorouracil or CPT-11, causing substantial tumor regression or complete tumor ablation. Thus, Apo2L may have potent anticancer activity without significant toxicity toward normal tissues.
Insights
Apo2 ligand (Apo2L) shows potent anticancer activity by inducing tumor cell apoptosis. This novel cancer therapy demonstrates minimal toxicity to normal tissues and synergizes with chemotherapy for significant tumor regression.
Area of Science:
- Molecular Biology
- Cancer Research
- Immunology
Background:
- Tumor necrosis factor (TNF) and Fas ligand induce apoptosis but cause severe toxicity.
- Apo2 ligand (Apo2L/TRAIL) is a related molecule with potential for cancer therapy.
- Apo2L's widespread mRNA expression suggests lower toxicity to normal cells.
Purpose of the Study:
- To investigate the therapeutic potential of Apo2L in cancer treatment.
- To assess the toxicity and efficacy of a soluble, bacterially-produced Apo2L.
- To evaluate Apo2L's synergistic effects with chemotherapy.
Main Methods:
- Generated a soluble, active form of human Apo2L in bacteria.
- Tested Apo2L's in vitro apoptosis induction on normal and cancer cell lines.
- Administered Apo2L intravenously to nonhuman primates and in mice with tumor xenografts.
- Evaluated Apo2L's effects alone and in combination with 5-fluorouracil or CPT-11.
Main Results:
- Normal cells showed resistance to Apo2L-induced apoptosis in vitro.
- Nonhuman primates exhibited no detectable toxicity after repeated Apo2L injections.
- Apo2L demonstrated cytostatic/cytotoxic effects on 32/39 cancer cell lines.
- Apo2L reduced tumor incidence in mice and induced apoptosis in established tumors.
- Synergistic tumor regression and ablation were observed when Apo2L was combined with chemotherapy.
Conclusions:
- Apo2L exhibits potent anticancer activity with a favorable safety profile.
- Apo2L effectively targets tumor cells while sparing normal tissues.
- Apo2L represents a promising therapeutic agent for cancer treatment, especially in combination therapy.
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