Clinical efficacy and toxicity of doxorubicin encapsulated in glutaraldehyde-treated erythrocytes administered to dogs with lymphosarcoma

Curt M. Matherne From the Department of Veterinary Resources, The University of Texas M. D. Anderson Cancer Center, Science Park, Bastrop, TX 78602 (Matherne, Satterfield, Schmidt), the Institute of Biological Chemistry, University of Genoa, Italy (Gasparini, Tonetti), and the Agricultural Research Service, Food Animal Protection Research Laboratory, USDA, College Station, TX 77845 (Astroff, Rowe, DeLoach).

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William C. Satterfield From the Department of Veterinary Resources, The University of Texas M. D. Anderson Cancer Center, Science Park, Bastrop, TX 78602 (Matherne, Satterfield, Schmidt), the Institute of Biological Chemistry, University of Genoa, Italy (Gasparini, Tonetti), and the Agricultural Research Service, Food Animal Protection Research Laboratory, USDA, College Station, TX 77845 (Astroff, Rowe, DeLoach).

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Anna Gasparini From the Department of Veterinary Resources, The University of Texas M. D. Anderson Cancer Center, Science Park, Bastrop, TX 78602 (Matherne, Satterfield, Schmidt), the Institute of Biological Chemistry, University of Genoa, Italy (Gasparini, Tonetti), and the Agricultural Research Service, Food Animal Protection Research Laboratory, USDA, College Station, TX 77845 (Astroff, Rowe, DeLoach).

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Michela Tonetti From the Department of Veterinary Resources, The University of Texas M. D. Anderson Cancer Center, Science Park, Bastrop, TX 78602 (Matherne, Satterfield, Schmidt), the Institute of Biological Chemistry, University of Genoa, Italy (Gasparini, Tonetti), and the Agricultural Research Service, Food Animal Protection Research Laboratory, USDA, College Station, TX 77845 (Astroff, Rowe, DeLoach).

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A. Barry Astroff From the Department of Veterinary Resources, The University of Texas M. D. Anderson Cancer Center, Science Park, Bastrop, TX 78602 (Matherne, Satterfield, Schmidt), the Institute of Biological Chemistry, University of Genoa, Italy (Gasparini, Tonetti), and the Agricultural Research Service, Food Animal Protection Research Laboratory, USDA, College Station, TX 77845 (Astroff, Rowe, DeLoach).

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Russell D. Schmidt From the Department of Veterinary Resources, The University of Texas M. D. Anderson Cancer Center, Science Park, Bastrop, TX 78602 (Matherne, Satterfield, Schmidt), the Institute of Biological Chemistry, University of Genoa, Italy (Gasparini, Tonetti), and the Agricultural Research Service, Food Animal Protection Research Laboratory, USDA, College Station, TX 77845 (Astroff, Rowe, DeLoach).

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Loyd D. Rowe From the Department of Veterinary Resources, The University of Texas M. D. Anderson Cancer Center, Science Park, Bastrop, TX 78602 (Matherne, Satterfield, Schmidt), the Institute of Biological Chemistry, University of Genoa, Italy (Gasparini, Tonetti), and the Agricultural Research Service, Food Animal Protection Research Laboratory, USDA, College Station, TX 77845 (Astroff, Rowe, DeLoach).

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John R. DeLoach From the Department of Veterinary Resources, The University of Texas M. D. Anderson Cancer Center, Science Park, Bastrop, TX 78602 (Matherne, Satterfield, Schmidt), the Institute of Biological Chemistry, University of Genoa, Italy (Gasparini, Tonetti), and the Agricultural Research Service, Food Animal Protection Research Laboratory, USDA, College Station, TX 77845 (Astroff, Rowe, DeLoach).

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Summary

Doxorubicin was encapsulated in canine erythrocytes, treated with 0.32% glutaraldehyde, and administered at a dosage equivalent to 30 mg of free doxorubicin/m2 of body surface area to dogs with diagnosis of lymphosarcoma. Compared with administration of free doxorubicin, this method of drug delivery substantially reduced peak plasma concentration and prolonged higher plasma concentration of doxorubicin. As such, this method was comparable to continuous iv infusion. Previous studies have indicated this method’s potential for reduction in toxic side effects, particularly cardiotoxicosis, while allowing higher total doses of doxorubicin to be administered. In this study, doxorubicin encapsulated in glutaraldehyde-treated erythrocytes induced a triphasic exponential decay of doxorubicin from plasma, the highest relative contribution to the total area of the curve being the terminal phase. The treatment was effective in inducing complete and partial remissions of lymphosarcoma, with minimal acute toxicosis and no evidence of cardiotoxicosis. However, substantial, unanticipated, chronic, nonregenerative myelosuppression developed, and was most strikingly expressed as profound thrombocytopenia. Efforts to ameliorate or circumvent this toxic effect will be required prior to further consideration of this doxorubicin delivery system for treatment of systemic neoplasia.

Summary

Doxorubicin was encapsulated in canine erythrocytes, treated with 0.32% glutaraldehyde, and administered at a dosage equivalent to 30 mg of free doxorubicin/m2 of body surface area to dogs with diagnosis of lymphosarcoma. Compared with administration of free doxorubicin, this method of drug delivery substantially reduced peak plasma concentration and prolonged higher plasma concentration of doxorubicin. As such, this method was comparable to continuous iv infusion. Previous studies have indicated this method’s potential for reduction in toxic side effects, particularly cardiotoxicosis, while allowing higher total doses of doxorubicin to be administered. In this study, doxorubicin encapsulated in glutaraldehyde-treated erythrocytes induced a triphasic exponential decay of doxorubicin from plasma, the highest relative contribution to the total area of the curve being the terminal phase. The treatment was effective in inducing complete and partial remissions of lymphosarcoma, with minimal acute toxicosis and no evidence of cardiotoxicosis. However, substantial, unanticipated, chronic, nonregenerative myelosuppression developed, and was most strikingly expressed as profound thrombocytopenia. Efforts to ameliorate or circumvent this toxic effect will be required prior to further consideration of this doxorubicin delivery system for treatment of systemic neoplasia.

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