CONICET | Buscador de Institutos y Recursos Humanos

Doxorubicin is commonly used in the treatment of several cancers, including breast and ovarian cancers. In spite of the development of modern therapeutic strategies, chemotherapy is still the treatment of choice for breast carcinomas resistant to endocrine therapy. The aim of this project was a) to evaluate the effect of doxorubicin in experimental hormone-responsive and unresponsive carcinomas, b) to evaluate if hormone resistance was associated with drug resistance and c) to test endocrine therapy in combination with doxorubicin. The tumors used were ductal metastatic mammary carcinomas expressing high levels of estrogen and progesterone receptors which show different degrees of hormone responsiveness. They have been induced in BALB/c mice by medroxyprogesterone acetate. Free doxorubicin (doxo) and commercial pegylated liposomes containing doxorubicin obtained from Schering-Plough (Cx) or Laboratorios Raffo (Dg), were used. The human ovarian carcinoma cell line SKOV-3, transplanted in nude mice was used as positive control of doxorubicin responsiveness. Eleven days after s.c. transplantation, when tumors were already palpable, mice were treated i.v. with either doxo, Cx or Dg in doses of 18 or 9mg/kg body weight once a week during 1 month. Liposome vehicle was used in controls. High doses of Cx or Dg, inhibited tumor growth, but showed evident signs of toxicity (body weight loss, cardiotoxicity, skin lesions and histopathological evaluation); doxo induced a delay in tumor growth, and more severe signs of toxicity. Interestingly, the lower dose of Cx or Dg had similar therapeutic effects than the higher dose but inducing almost no toxicity. We then selected two mifepristone and 17-â-estradiol-responsive mammary carcinomas, C4-HI and CC4-3-HI, and one variant, C4-2-HI, which is unresponsive to both and we used the same experimental design as explained above. Treatments were started 4 or 11 days after tumor transplantation. The three tumors responded similarly to the chemotherapy. Doxo showed higher side effects than the liposome forms and no differences were registered between Cx or Dg-treated animals. Mice carrying C4-HI tumors of about 50 mm2, were treated with the lower dose of Dg, plus/or the antiprogestin mifepristone (12 mg/kg/day, s.c.) or 5 mg 17- is unresponsive to both and we used the same experimental design as explained above. Treatments were started 4 or 11 days after tumor transplantation. The three tumors responded similarly to the chemotherapy. Doxo showed higher side effects than the liposome forms and no differences were registered between Cx or Dg-treated animals. Mice carrying C4-HI tumors of about 50 mm2, were treated with the lower dose of Dg, plus/or the antiprogestin mifepristone (12 mg/kg/day, s.c.) or 5 mg 17- â-estradiol-responsive mammary carcinomas, C4-HI and CC4-3-HI, and one variant, C4-2-HI, which is unresponsive to both and we used the same experimental design as explained above. Treatments were started 4 or 11 days after tumor transplantation. The three tumors responded similarly to the chemotherapy. Doxo showed higher side effects than the liposome forms and no differences were registered between Cx or Dg-treated animals. Mice carrying C4-HI tumors of about 50 mm2, were treated with the lower dose of Dg, plus/or the antiprogestin mifepristone (12 mg/kg/day, s.c.) or 5 mg 17-2, were treated with the lower dose of Dg, plus/or the antiprogestin mifepristone (12 mg/kg/day, s.c.) or 5 mg 17- â-estradiol pellets. Combined treatments induced a better therapeutic effect than single treatments (p<0.05). We can conclude that a) no differences were observed between both liposome formulations, b) the impressive therapeutic effects observed with the lower dose of Cx or Dg used, suggests that side effect can be minimized by using lower doses, c) the MPA murine breast cancer model is appropriate for chemotherapeutic drug screening either alone or in combination with endocrine therapy. that a) no differences were observed between both liposome formulations, b) the impressive therapeutic effects observed with the lower dose of Cx or Dg used, suggests that side effect can be minimized by using lower doses, c) the MPA murine breast cancer model is appropriate for chemotherapeutic drug screening either alone or in combination with endocrine therapy. -estradiol pellets. Combined treatments induced a better therapeutic effect than single treatments (p<0.05). We can conclude that a) no differences were observed between both liposome formulations, b) the impressive therapeutic effects observed with the lower dose of Cx or Dg used, suggests that side effect can be minimized by using lower doses, c) the MPA murine breast cancer model is appropriate for chemotherapeutic drug screening either alone or in combination with endocrine therapy.