NSC 290205-based therapy in colon 38 adenocarcinoma in combination with adriamycin (ADR)

Abstract

15104 Background: NSC 290205 (A) is a hybrid synthetic antitumor ester which combines a D-lactam derivative of androsterone and nitrogen mustard. In this study cyclophosphamide in the standard CHOP chemotherapeutic regimen was replaced with NSC 290205 (AHOP) and the efficacy of these regimens against murine colon 38 adenocarcinoma was compared. Methods: Colon 38 adenocarcinoma was used in this study. It was purchased from NCI (USA). Tumor was grown in C57 Bl mice and was transplanted subcutaneously with puncture in the inguinal region. The amount of the transplanted graft was 40–50 mg fragment. The acute toxicity of the compounds was determined and the lethal dose LD10 was used as a therapeutic dose. The antitumor activity was assessed from the inhibition of tumor growth by volume in cm3 and T/C % oncostatic parameter, according to the protocol of the experimental evaluation of anticancer drugs of the NCI. Treatment was given as an intermitted dose on days 1, 5, 9. Results: Results show that treatment with steroidal derivative (A) or cyclophosphamide (C) produced almost equal borderline activity. Moreover, both CHOP and AHOP regimens showed significant and comparable antitumor effect. AHOP caused the maximum effect inhibiting tumor growth by 68.5 % and producing T/C values of 211%. CHOP was less effective producing 47.1% inhibition of tumor growth and T/C 174%. Conclusions: Although the treatment of colon adenocarcinoma with cyclophosphamide or NSC 290205 yielded equivalent results, AHOP showed higher antitumor potency than CHOP. It is very likely that the D-lactamic steroid (androstan) alkylator for A, containing the amide group -NH-CO-, combined with adriamycin which intercalates between DNA base-pairs, is the explanation for the higher activity of AHOP as compared to CHOP. Preclinical research supports that the aza-steroidal alkylator NSC 290205 demonstrates favorable acute and sub acute toxicity, as well as superior antitumor activity which in combination with adriamycin against colon 38 adenocarcinoma justifies further clinical studies. No significant financial relationships to disclose.