Summary
This article gives a comprehensive survey on the anticancer activity of nitrosoureas linked to steroidal androgens in methylnitrosourea (MMU)-induced rat mammary carcinoma. cis-Androsterone, testosterone, 19-nortestosterone and 5-α-dihydrotestosterone were used as carrier hormones and were linked to various cytotoxic N-[N′-(2-chloroethyl)-N′-nitrosocarbamoyl] (CNC)-aminoacids and to N-(2-hydroxyethyl)-N′-(2-chloroethyl)-N′-nitrosourea hemisuccinate (HECNU-hemisuccinate). In the MNU-model used esters of dihydrotestosterone (DHT) invariably were more active and less toxic than those of testosterone, nortestosterone and cis-androsterone. Within the DHT esters of CNC-aminoacids those of CNC-glycine, CNC-methionine and CNC-alanine showed the highest antineoplastic activities and superiority compared with equimolar dosages of their unlinked mixtures. Additionally, CNC-alanine-DHT ester had the highest therapeutic ratio of all agents investigated. HECNU-hemisuccinate-DHT ester, on the other hand, achieved even higher antitumor activity at the optimal dose but had a narrower therapeutic ratio.
No obvious correlation between antineoplastic efficacy and receptor binding affinity could be demonstrated, but, to be active, a conjugate apparently had to have some receptor binding affinity for both androgen and progesterone receptors. The results obtained indicate that linking antineoplastic agents to transport molecules with affinity to steroid receptors is a highly promising approach to obtain drugs with specific activity in steroid receptor containing tumors.
Similar content being viewed by others
Abbreviations
- CNC:
-
N-[N′-(2-chloroethyl)-N′-nitrosocarbamoyl]
- DHT:
-
dihydrotestosterone
- HECNU:
-
N-(2-hydroxyethyl)-N′-(2-chloroethyl)-N′-nitrosourea
- MNU:
-
methylnitrosourea
References
Allegra JC, Lippman ME, Thompson EB, Simon R, Barlock A, Green L, Huff KK, Do HMT, Aitken SC (1979) Distribution, frequency, and quantitative analysis of estrogen, progesterone, androgen, and glucocorticoid receptors in human breast cancer. Cancer Res 39:1447–1454
Arafah BM, Gullino PM, Manni A, Pearson OH (1980) Effect of ovariectomy on hormone receptors and growth ofN-nitrosomethylurea-induced mammary tumors in the rat. Cancer Res. 40:4628–4630
Arafah BM, Finegan HM, Roe J, Manni A, Pearson OH (1982) Hormone dependency in N-Nitrosomethylurea-induced rat mammary tumors. Endocrinology 111:584–588
Berger MR, Zeller, WJ (1988) Interaction of nicotine with anticancer treatment. Klin Wochenschr 66:127–133
Berger MR, Habs M, Schmähl D (1983) Noncarcinogenic chemotherapy with a combination of vincristine, methotrexate and 5-fluorouracil (VMF) in rats. Int Cancer 32:231–236
Berger MR, Floride J, Schmähl D, Schreiber J, Eisenbrand G (1986) Estrogen-linked 2-chloroethylnitrosoureas: anticancer efficacy in MNU-induced rat mammary carcinoma, uterine activity in mice and receptor interactions. Eur J Cancer Clin Oncol 22:1179–1191
Betsch B, Berger MR, Spiegelhalder B, Eisenbrand G, Schmähl D (1989) New estradiol-linked nitrosoureas: can the pharmacokinetic properties help to explain the pharmacodynamic activities? Eur J Cancer Clin Oncol 25:105–111
Betsch B, Berger MR, Spiegelhalder B, Schmähl D, Eisenbrand G (1990) New estradiol-linked nitrosoureas: Are there perspectives for a site-directed chemotherapy of estradiol-receptor positive mammary carcinomas? Eur J Cancer Clin Oncol (in press)
Blankenstein MA, Blaauw G, van't Verlaat JW, van der Meulen-Dijk C, Thijssen JHH (1987) Steroid receptors in cerebral tumours. Possible consequence for endocrine treatment? In: Klijn JlGM et al. (eds) Hormonal manipulation of cancer: peptides, growth factors, and new(anti)steroidal agents. Raven, New York, pp 61–70
Corr R, Berger MR, Betsch B, Floride JA, Brix HP, Schmähl D (1990) Modulation of cytosolic sexual steroid receptors in autochthonous methylnitrosourea-induced rat mammary carcinoma following application of 2-chloroethylnitrosocarbamoyl-L-alanine linked to oestradiol or dihydrotestosterone. Br J Cancer 62:42–47
Ehresmann K, Zelezny O, Eisenbrand G (1984) Synthesis of potentially antineoplastic amides and esters ofN-[N′-(2-chloroethyl)-N;-nitrosocarbamoyl] amino acids: II. Arch Pharm (Weinheim) 317:481–487
Eisenbrand G, Fiebig HH, Zeller WJ (1976) Some new congeners of the anticancer agent BCNU. Z Krebsforsch 86:279–286
Eisenbrand G, Berger MR, Brix JE, Fischer J, Mühlbauer K, Nowrousian MR, Przybilski M, Schneider MR, Stahl W, Tang W, Zelezny O, Zeller WJ (1989) Nitrosoureas. Mode of action and perspectives in the use of hormone receptor affine carrier molecules. Acta Oncol 28:203–211
Fischer J (1988) Synthese von steroid-verknüpftenN-[N′-(2-Chlorethyl)-N′-nitrosocarbamoyl]-aminosäurederivaten und Untersuchung ihrer biologischen Wirkung. PhD Thesis, University of Kaiserslautern
Hassner A, Alexanian V (1978) Direct room temperature esterification of carboxylic acid. Tetrahedron Lett 46:4475–4478
Havemann K, Maasberg M, Rotsch M, Jaqnes G, Enderele-Schmidt U, Weehle R, Wolf M (1989) The possible role of androgens in small cell lung cancer (SCLC). Cancer Res Clin Oncol 115 [Suppl]:30
Klenner T, Berger MR, Eisenbrand G, Schmähl D (1989) Anticancer efficacy of 2-chloroethylnitrosocarbamoyl derivatives of L-alanine, glycine, their di- and tripeptide homologues and the respective amides in methylnitrosurea-induced rat mammary carcinoma Br J Cancer 59:335–340
Koziol AJ, Donna AM (1981) A distribution-free test for tumor growth curve analysis with application to an animal tumour immunotherapy experiment. Biometrics 37:383–390
Kranzfelder G, Schneider M, von Angerer E, Schönenberger H (1980) Entwicklung neuer Antiöstrogene vom Typ der 3.3′-Dihydroxy-β-diaethylstilbens und ihre Prüfung am DMBA-induzierten hormonabhängigen Mammacarcinom der SD-Ratte. J Cancer Res Clin Oncol 97:167–186
Lea OA, Kvinnsland S, Thorsen T (1989) Improved measaurement of androgen receptors in human breast cancer. Cancer Res 49:7162–7167
Rochefort H, Garcia M (1980) Interactions and actions of androgens on the estrogen receptor. In. Genazzani E et al. (eds) Pharmacological modulation of steroid action. Raven, New York, pp 75–80
Schieder K, Koelbl H, Bieglmayer C, Breitenecker G (1987) Heterogenity of steroid receptors in endometrial and ovarian malignancies. Tumor Diagn. Ther 8:171–176
Schneider MR, von Angerer E, Höhn W, Sinowatz F (1987) Antitumor activity of antiestrogenic phenylindoles on experimental prostate tumors. Eur J Cancer Clin Oncol 23:1005–1015
Schneider MR, Schuderer ML (1990) 1-[4-(N,N-Bis-β-chloroethylcarbamoyloxy)-phenyl]-1,2-bis-(hydroxyphenyl)-but-1-enes: drugs specifically targeted against estrogen receptor positive mammary tumors. Arch Pharm 323:215–219
Sica V, Nola E, Contieri E, Bova R, Masucci MT, Medici N, Petrillo A, Weisz A, Molinari AM, Pucca GA (1984) Estradiol and progesterone receptors in malignant gastrointestinal tumors. Cancer Res 44:4670–4674
Staab HA, Mannschreck A (1962) Synthese von Carbonsäureestern nach Imidazolidmethode. Chem Ber 95:1284–1297
Tang WC, Eisenbrand G (1981) Synthesis of potentially antineoplastic derivatives ofN-{N′-(2-chloroethyl)-N′-nitrosocarbamoyl} amino acids. Arch Pharm (Weinheim) 314:910–917
Venditti JM (1981) Preclinical drug development:rationale and methods. Semin Oncol 8:349–361
von Angerer E, Strohmeier J (1987) 2 Phenylindoles. Effect ofN-benzylation on estrogen receptor affinity, estrogenic properties, and mammary tumor inhibiting activity. J Med Chem 30:131–136
Author information
Authors and Affiliations
Additional information
Dedicated to Professor Dr. D. Schmähl on the occasion of his 65th birthday
Rights and permissions
About this article
Cite this article
Brix, H.P., Berger, M.R., Schneider, M.R. et al. Androgen-linked alkylating agents: biological activity in methylnitrosourea-induced rat mammary carcinoma. J Cancer Res Clin Oncol 116, 538–549 (1990). https://doi.org/10.1007/BF01637072
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01637072