PURPOSE: We tested 3 alkylating esters of D-lactam androsterone, 3 alkylating esters of A-lactam testosterone and the alkylating nitrogen mustard components of these esters, for antineoplastic activity on non-small cell lung carcinoma (NSCLC) in vitro and in vivo. MATERIALS AND METHODS: Cytostatic and cytotoxic activity was evaluated in vitro against 10 human NSCLC cell lines. The in vitro testing was performed with the MTT metabolic-colorimetric assay and the mean concentrations of each drug that generated 50% or total (100%) growth inhibition (GI50 and TGI, respectively) as well as the drug concentrations that produced cytotoxicity against 50% of the cultured cells (IC50) were calculated. Furthermore, the in vivo antitumour effect was determined against the relatively chemo-resistant Lewis lung carcinoma (LLC) on mice. The acute toxicity of the tested compounds was appointed in C57BL mice and the antitumor effect on LLC was assessed from the percent increase in median lifespan of the treated animals over the untreated (control) (T/C%). RESULTS: The lactam steroidal esters presented lower toxicity and increased antineoplastic activity in vitro and in vivo compared to their respective alkylating components. An A-lactam testosterone ester namely: 17beta-hydroxy- 3-aza-A-homo-4alpha-androsten-4-one-p-N,N-bis (2chloroethyl) amino phenoxy acetate (ALT-CAPOA) performed significantly higher anticancer activity in vitro and in vivo. This compound generated 37.5% 90-day disease free survivors (cures) against LLC. CONCLUSION: These results indicate a high antitumor potential of lactam steroid alkylating esters depended on the alkylating moiety as well as on the modified steroidal carrier. Preclinical research supports that ALT-CAPOA generates well-tolerated toxicity as well as superior antitumor activity against NSCLC. These significant results call for further clinical development.
PURPOSE: We tested 3 alkylating esters of D-lactam androsterone, 3 alkylating esters of A-lactamtestosterone and the alkylating nitrogen mustard components of these esters, for antineoplastic activity on non-small cell lung carcinoma (NSCLC) in vitro and in vivo. MATERIALS AND METHODS: Cytostatic and cytotoxic activity was evaluated in vitro against 10 humanNSCLC cell lines. The in vitro testing was performed with the MTT metabolic-colorimetric assay and the mean concentrations of each drug that generated 50% or total (100%) growth inhibition (GI50 and TGI, respectively) as well as the drug concentrations that produced cytotoxicity against 50% of the cultured cells (IC50) were calculated. Furthermore, the in vivo antitumour effect was determined against the relatively chemo-resistant Lewis lung carcinoma (LLC) on mice. The acute toxicity of the tested compounds was appointed in C57BL mice and the antitumor effect on LLC was assessed from the percent increase in median lifespan of the treated animals over the untreated (control) (T/C%). RESULTS: The lactam steroidal esters presented lower toxicity and increased antineoplastic activity in vitro and in vivo compared to their respective alkylating components. An A-lactam testosterone ester namely: 17beta-hydroxy- 3-aza-A-homo-4alpha-androsten-4-one-p-N,N-bis (2chloroethyl) amino phenoxy acetate (ALT-CAPOA) performed significantly higher anticancer activity in vitro and in vivo. This compound generated 37.5% 90-day disease free survivors (cures) against LLC. CONCLUSION: These results indicate a high antitumor potential of lactam steroid alkylating esters depended on the alkylating moiety as well as on the modified steroidal carrier. Preclinical research supports that ALT-CAPOA generates well-tolerated toxicity as well as superior antitumor activity against NSCLC. These significant results call for further clinical development.