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Anti-tumor effects of nitrosylcobalamin against spontaneous tumors in dogs

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An Erratum to this article was published on 03 May 2011

Summary

Purpose: Given the limited options available to treat canine cancers, the use of companion animals for evaluating new drugs may identify better therapies for veterinary and human oncology. The anti-tumor effects of nitrosylcobalamin (NO-Cbl), an apoptosis-inducing, vitamin B12-based carrier of nitric oxide (NO), was evaluated in four dogs with spontaneous cancer. Experimental Design: (1) A 13 year-old female spayed Giant Schnauzer with inoperable thyroid carcinoma and hypercalcemia. (2) A 6 year-old male neutered Golden Retriever with a malignant peripheral nerve sheath tumor (MPNST). (3) A ten yr-old neutered male Bichon Frise with apocrine gland anal sac adenocarcinoma (AGACA). (4) A 7 year-old female spayed Labrador mix with spinal meningioma following partial surgical resection. Tumor regression was measured by physical exam and verified using ultrasound (case 1) and MRI (case 2–4). Serum chemistries and hematologic parameters were monitored throughout the studies. Results: (1) The Giant Schnauzer demonstrated a 77% reduction in tumor volume after ten weeks of daily NO-Cbl treatment. (2) The Golden Retriever demonstrated a 53% reduction in tumor volume after 15 months of daily NO-Cbl therapy. (3) The Bichon Frise demonstrated a 43% regression of the primary tumor and a 90% regression of an iliac lymph node measured by MRI after 15 months of treatment. After 61 months, the dog currently has stable disease, normal liver enzymes, CBC analysis, and no evidence of toxicity. (4) The Labrador demonstrated complete regression of the residual tumor after 6 months of treatment. Conclusion: We have shown previously that NO-Cbl is endocytosed by malignant cells, resulting in intra-tumoral NO release. In this study, we have shown that daily long-term use of NO-Cbl induced responses in all dogs without any signs of toxicity. The use of NO-Cbl capitalizes on the tumor-specific properties of the vitamin B12 receptor and represents a promising anti-cancer therapy.

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Abbreviations

AGACA:

Apocrine gland anal sac adenocarcinoma

Apo2L/TRAIL:

Tumor necrosis factor-related apoptosis-inducing ligand

MPNST:

Malignant peripheral nerve sheath tumor

SM:

Spinal meningioma

TCII:

Transcobalamin II

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Statement of Translational Relevance

Currently, the NCI’s Comparative Oncology Program (COP) is evaluating the anti-tumor efficacy of chemotherapeutic agents in dogs with spontaneous occurring tumors. The impetus for this program stemmed from the high discordance of chemotherapeutic agent response rates observed in xenograft studies to the frequently low rates observed with the same agent in clinical studies. Our work is innovative because it involves the use of “biological Trojan horse technology” to target cancer. Since the 1950’s researchers have tried in vain to synthesize cobalamin analogs as anti-tumor agents, utilizing the vitamin B12 receptor (transcobalamin II receptor, TC II-R) or methionine synthase as a target. We synthesized a vitamin B12 based compound that delivers nitric oxide to cells. We have demonstrated previously that cancer cells which overexpress the vitamin B12 receptor (TCII-R) are very sensitive to nitrosylcobalamin (NO-Cbl). Our case studies demonstrate anti-tumor efficacy with limited toxicity to normal tissues. NO-Cbl sensitizes multidrug-resistant cancer cells to the antitumor effects of several different cytotoxic drugs and may therefore be valuable when utilized in combination regimens.

Acknowledgments

Special thanks to Dr. Christine R. Anderson (Angell Animal Medical Center, Boston, MA) for her care and monitoring of the Bichon Frise. Special thanks to Dr. Steven Scott (Akron-Peninsula Veterinary Office, Akron, OH) for his care and monitoring of the Golden Retriever. We also thank Dr. Jean M. Poulson (Tufts University School of Veterinary Medicine, North Grafton, MA) for her assistance with the imaging studies for the Bichon Frise. A very special thanks to Kim Darusz (PetsDx) for freely giving her time, energy, enthusiasm and continued support of our program. Financial Support: This work was supported by gifts from Crandall B. and Beverly Huckins, the Reuter Foundation, Valley Save-a-Pet and PetsDx to J.A.B.

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Authors and Affiliations

  1. Bauer Research Foundation, Akron Innovation Campus, 411 Wolf Ledges Pkwy, suite 105, Akron, OH, 44311, USA

    Joseph A. Bauer

  2. PetsDx Veterinary Imaging, Pittsburgh, PA, 15237, USA

    Gerald Frye

  3. PetRays Veterinary Radiology Consultants, Spring, TX, 77386, USA

    Anne Bahr

  4. Department of Veterinary Clinical Sciences, The Ohio State University, Columbus, OH, 43210, USA

    Jennifer Gieg

  5. Carolina Veterinary Specialists Medical Center, Charlotte, NC, 28273, USA

    Peter Brofman

Authors
  1. Joseph A. Bauer
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  2. Gerald Frye
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  3. Anne Bahr
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  4. Jennifer Gieg
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  5. Peter Brofman
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Corresponding author

Correspondence to Joseph A. Bauer.

Additional information

An erratum to this article can be found at http://dx.doi.org/10.1007/s10637-011-9664-y

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Bauer, J.A., Frye, G., Bahr, A. et al. Anti-tumor effects of nitrosylcobalamin against spontaneous tumors in dogs. Invest New Drugs 28, 694–702 (2010). https://doi.org/10.1007/s10637-009-9282-0

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