A comparison of locoregional depot and systemic preparations of 9-aminocamptothecin for treatment of liver metastases in a rat tumor model: superior antitumor activity of sustained-release preparation.

Abstract

BACKGROUND:

Locoregional therapy of hepatic-metastatic disease may overcome the limitations of systemic therapy by allowing tumor drug dose intensification without increasing systemic toxicity. This may result in improved efficacy. We have demonstrated that the novel topoisomerase I inhibitor 9-Aminocamptothecin (9-AC) when dissolved in Ethiodol acts as a sustained release preparation, with good antitumor activity. Its benefit as a depot hepatic intraarterial (i.a.) therapy for hepatic metastases was compared to systemic therapy with an aqueous colloidal dispersion (CD) preparation of 9-AC in a rat model, since a lack of demonstrable benefit of the locoregional therapy, would argue against further clinical evaluation.

METHODS:

Fisher rats underwent direct intraportal injection of 2 x 10(5) MADB106 adenocarcinoma cells and were treated 6 to 7 days later with: (a) bolus i.a. 9-AC (60 micrograms) in 60 microliters of Ethiodol; (b) bolus i.a. CD/9-AC (60 micrograms) in 200 microliters water; (c) bolus i.a. Ethiodol only (60 microliters), or (d) CD/9-AC (60 micrograms) in 200 microliters water, via a mini-osmotic pump pumping at 1 microliter/hr for 7 days intraperitoneally (i.p.). Livers were harvested 10 to 12 days later, and the number of metastases on the surface were counted blindly.

RESULTS:

Bolus hepatic i.a. 9-AC/Ethiodol was found to be significantly superior in reducing the number of hepatic metastases, when compared to the aqueous CD preparation administered in the same manner, or by continuous infusion via mini-osmotic pump i.p. (p < 0.01). Systemic therapy was also associated with substantial toxicity.

CONCLUSIONS:

These results suggest that locoregional therapy of hepatic neoplasms with 9-AC/Ethiodol would be associated with clinical efficacy far exceeding that associated with its systemic administration.

• Authors: K A Dookeran, A Brumfield, J T Rubin
• Journal: Annals of surgical oncology (Ann Surg Oncol) Vol. 4 Issue 4 Pg. 355-60 (Jun 1997) ISSN: 1068-9265 [Print] United States
• PMID: 9181237 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Antineoplastic Agents
• Delayed-Action Preparations
• 9-aminocamptothecin
• Ethiodized Oil
• Camptothecin

Topics

• Animals
• Antineoplastic Agents (administration & dosage, therapeutic use)
• Camptothecin (administration & dosage, analogs & derivatives, therapeutic use)
• Delayed-Action Preparations
• Disease Models, Animal
• Drug Delivery Systems
• Ethiodized Oil (therapeutic use)
• Liver Neoplasms, Experimental (drug therapy, secondary)
• Rats
• Rats, Inbred F344