New Doxorubicin Analogs Active against Doxorubicin-resistant Colon Tumor Xenografts in the Nude Mouse1

The antitumor activity of doxorubicin and three new deriva tives modified on the position 4' of the amino sugar was tested against five human colon tumors and two human rectal tumors (originating from different patients) and xenografted into nude mice. The drugs tested were: 4'-epidoxorubicin; 4'-deoxydoxorubicin; and 4'-O-methyldoxorubicin. Mice were treated i.v. on a weekly basis for 3 to 4 weeks, starting when the tumors were well established (advanced stage of tumor treatment). No statistically significant effect was observed against the tumors tested with the drugs doxorubicin and 4'-epidoxorubicin. 4'Deoxydoxorubicin was active against all the colon tumors tested (4 of 5 statistically significant), and 4'-O-methyldoxorubicin was active against 4 of 5 colon tumors tested (statistically significant). Overall, the activity of 4'-O-methyldoxorubicin was less than that of 4'-deoxydoxorubicin against the colon carci nomas tested. Neither analog was active against the two rectal carcinomas tested. The results of these studies indicate that: (a) the modifica tions in the chemical structure of doxorubicin can alter the biological properties and thus create new drugs varying in activity against different human tumors; (b) the two antracycline derivatives, 4'-deoxydoxorubicin and 4'-O-methyldoxorubicin, appear to be good candidates for clinical trial against colon carcinoma; and (c) the nude mice system can offer a great potential for identification of new anthracycline analogs and, in general, new anticancer agents of clinical interest.