ABSTRACT
The authors present results obtained in a complex study of 17alpha-acetoxy-3beta-butanoyloxy-6-methyl-pregna-4,6-dien-20-on (ABMP). ABMP was shown to differ from existing analogues by high gestagen activity and prolonged action. The substance does not possess androgenic or mineralocorticoid activity, is not toxic when used in high doses, and possesses significant cytostatic and chemiosensitizing activity. These properties of ABMP demonstrate that the substance should be studied in clinical setting as a gestagen with anticancer and chemiosensitizing activity for further application to therapy of hyperplastic processes in the female genital system and tumors that are sensitive to female sex hormones.
Subject(s)
17-alpha-Hydroxyprogesterone/analogs & derivatives , Drug Evaluation , Neoplasms/drug therapy , 17-alpha-Hydroxyprogesterone/therapeutic use , Animals , Cell Proliferation/drug effects , Humans , Neoplasms/pathology , Treatment OutcomeABSTRACT
Chemical modification of progesterone molecule leads to changes both in the gestagenic activity of new derivatives and in their specific binding with progesterone receptors. The passage from esters (acetomepregenole, butagest) to the corresponding OH-forms such as 17a-acetoxy-3b-hydroxy-6-methyl-pregna-4,6-dien-20-one (ABMP)is accompanied by an increase in the binding with progesterone receptors in vitro. The translocation of a double bond from endocyclic (N6-N7) to exocyclic position (methylene group at N6 in ABMP) has no significant effect on the ability to binding with progesterone receptors.
Subject(s)
Endometrium/metabolism , Progesterone Congeners/metabolism , Progestins/metabolism , Receptors, Progesterone/metabolism , 17-alpha-Hydroxyprogesterone/analogs & derivatives , 17-alpha-Hydroxyprogesterone/chemistry , 17-alpha-Hydroxyprogesterone/metabolism , Adult , Endometrial Hyperplasia/metabolism , Endometrial Hyperplasia/prevention & control , Female , Humans , Hydroxyprogesterones/chemistry , Hydroxyprogesterones/metabolism , Middle Aged , Pregnadienediols/chemistry , Pregnadienediols/metabolism , Pregnenes/chemistry , Pregnenes/metabolism , Progesterone Congeners/chemistry , Progestins/chemistry , Structure-Activity RelationshipABSTRACT
Antitumor activity of a new highly active promising gestagen 17alpha-acetoxy-3beta-butanoyloxy-6-methyl-pregna-4,6-dien-20-one (butagest) was studied in mice with model cervical carcinoma (RShM-5). The reference drug was medroxyprogesteron acetate (MPA, Depo Provera) used in clinics. The new preparation introduced perorally in a dose of 1 mg per mice inhibited the model tumor growth by 73%, which was 18% (p < 0.01) more effective than the action of the reference drug MPA. The effect of the new gestagen was also studied in vitro with respect to human breast carcinoma of the MCF-7 line and human cervical carcinoma HeLa. The viability of the tumor cells was studied during a 6-day incubation with the drug at a concentration of 10(-7)-10(-5) M (MTT test). The reference compounds were progesterone and MPA. These drugs suppressed the growth of both MCF-7 and, in higher concentrations, of HeLa. Butagest inhibited the growth of HeLa in all concentrations. Thus, the new gestagen 17alpha-acetoxy-3beta-butanoyloxy-6-methyl-pregna-4,6-dien-20-one is capable of suppressing the viability of human breast carcinoma and human cervical carcinoma, being comparable or even more effective than the reference drugs.
Subject(s)
17-alpha-Hydroxyprogesterone/analogs & derivatives , 17-alpha-Hydroxyprogesterone/therapeutic use , Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Carcinoma/drug therapy , Uterine Cervical Neoplasms/drug therapy , 17-alpha-Hydroxyprogesterone/pharmacology , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Humans , Medroxyprogesterone Acetate/pharmacology , Medroxyprogesterone Acetate/therapeutic use , Mice , Mice, Inbred CBA , Progestins/pharmacology , Progestins/therapeutic useABSTRACT
The combined cytostatic effect of doxorubicin and gestagens progesterone, medroxyprogesterone acetate, mecigestone, and butagest on doxorubicin-resistant and doxorubicin-sensitive human breast cancer MCF-7 cells was studied by the MTT assay. On the 6th day of incubation progesterone, medroxyprogesterone acetate, mecigestone, and butagest in high concentrations (10(-5) M) potentiated the cytostatic action of doxorubicin in sensitive and resistant cells by 30-50%. Potentiation of the cytostatic effect produced by doxorubicin in sensitive cells is related to intrinsic cytotoxic activity of gestagens. In resistant cells these changes are associated with potentiation of the effect of doxorubicin.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Breast Neoplasms/drug therapy , Doxorubicin/administration & dosage , Progestins/administration & dosage , Antibiotics, Antineoplastic/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Drug Resistance, Neoplasm , Drug Synergism , Humans , Progestins/chemistrySubject(s)
Collagen/therapeutic use , Dexamethasone/administration & dosage , Kanamycin/administration & dosage , Administration, Topical , Animals , Delayed-Action Preparations , Dexamethasone/metabolism , Drug Evaluation, Preclinical , Drug Therapy, Combination , Eye/metabolism , Eye Injuries/drug therapy , Kanamycin/metabolism , Kinetics , Rabbits , Time FactorsABSTRACT
It was shown in experiments on rats and rabbits that a new derivative of 17 alpha-acetoxyprogesterone--mepregnol diacetate--combined with ethinyl estradiol in varied doses and ratios elicits a pronounced contraceptive effect. This steroid combination exerts neither antigonadotropic nor antiovulatory action. The changes detected in the RNA content are apparently of importance in the mechanism of the drug effect on reproduction. A role has been demonstrated of the central cholino- and adrenoreactive systems in providing the contraceptive effect of decreased doses of ethinyl estradiol and mepregnole diacetate.
