An oestradiol-linked nitrosourea and site-directed chemotherapy in mammary carcinoma

Betsch, B.; Berger, Martin R.; Spiegelhalder, B; Schmähl, D.; Eisenbrand, Gerhard

doi:10.1016/0277-5379(90)90194-x

Cited by 7 publications

(8 citation statements)

References 7 publications

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“…Various aspects of the pharmacokinetics of the cytotoxic CENU− l -Ala-estradiol 17-ester 918 compared with those of CENU− l -Ala 572 were reported. − The amino acid−estradiol conjugate had a 3-fold longer terminal plasma half-life, three times larger volume of distribution, three times faster distribution following iv administration, and two times faster absorption after peroral administration. − The conjugate 918 was shown to have 636,638 a greater availability in all tissues of female rats studied, i.e. liver, lung, spleen, uterus, and mammary carcinoma.…”

Section: Steroid−amino Acid Conjugatesmentioning

confidence: 99%

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A Critical Appraisal of the Evolution ofN-Nitrosoureas as Anticancer Drugs

1997

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Section: Steroid−amino Acid Conjugatesmentioning

confidence: 99%

“…628,631,632 Furthermore, compound 572, the active metabolite of estradiol 17ester 918, was obtained by an enzymatic hydrolysis. 636 A greatly prolonged plasma half-life of the metabolite 572 could account [636][637][638] for the effective anticancer activity of the estradiol-L-alanine conjugate 918.…”

Section: Structure−activity Relationshipsmentioning

confidence: 99%

A Critical Appraisal of the Evolution ofN-Nitrosoureas as Anticancer Drugs

1997

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“…ing normal (uterus) and tumour (mammary carcinoma) tissues at more than two times higher concentrations and over five-fold longer periods of time than CNC-L-ala (Betsch et al, 1990). Compared to CNC-L-ala and its physical mixture with oestradiol, CNC-L-ala-E2 showed also superior activity against mammary carcinoma cells in vitro (Petru et al, 1988).…”

mentioning

confidence: 98%

“…The significantly altered pharmacodynamic activity of one of the steroid-linked nitrosoureas can mainly be explained by pharmacokinetic properties (Betsch et al, 1989). In comparison with the unlinked single agent CNC-L-ala the conjugate to oestradiol showed a three times faster tissue distribution and a three-fold longer half-life in plasma (167 min).…”

mentioning

confidence: 99%

“…Although the toxicity of the linked compounds was lower than that of their positive controls, their therapeutic ratio is still moderate. Nevertheless, therapeutically active concentrations can be achieved in receptor-positive tumour tissue (Betsch et al, 1990) and reduced overall toxicity of the conjugates allows repeated administrations within a reasonable period of time; both properties represent discernible progress in the development of targeting molecules and of nitrosoureas with increased therapeutic ratio. Obviously, drugs with higher binding affinity to the hormone receptors are needed, which will allow further dose reduction due to more specific antineoplastic activity.…”

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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

Corr

Berger²,

Betsch³

et al. 1990

Br J Cancer

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Summary This study concentrated on the influence of 2-chloroethylnitrosocarbamoyl-L-alanine (CNC-L-ala) linked to oestradiol (CNA-L-ala-E2) or dihydrotestosterone (CNC-L-ala-DHT) in position 17 of the respective steroid hormone on tumour growth and receptor kinetics of methylnitrosourea-induced rat mammary carcinoma. Both compounds almost completely arrested logarithmically growing mammary carcinoma of Sprague-Dawley rats: in the first week CNC-L-ala-E2 blocked the growth of these tumours by 92% compared to untreated control animals while, in animals treated with the physically equimolar mixture of CNC-L-ala and oestradiol (positive control), tumour growth was inhibited by 51% only. CNC-L-ala-DHT arrested the tumour growth in the first week by 95%, while the respective positive control (CNC-L-ala plus dihydrotestosterone) effected a growth inhibition of 71% compared to the untreated control. These results correlate well with the influence of both drugs on the cytosolic receptor content of sexual steroid hormones in the tumours. CNC-L-ala-E2 depleted the content of oestradiol receptors and kept it down for a week, while concomitantly the content of progesterone receptors increased considerably and that of androgen receptors showed a short-lived decrease. CNC-L-ala-DHT depleted androgen receptors as well as progesterone receptors. The content of androgen receptors remained low for a week, while that of progesterone receptors recovered within 8 days. The content of oestrogen receptors showed a moderate decrease.The average survival time of women suffering from metastasising mammary carcinoma has been about 19 months for more than 40 years (Patel et al., 1986; Petru & Schmiihl, 1987 al., 1979; Kimura, 1984;Longcope et al., 1980;Mohammed et al., 1986) of human cancers and in 85% (Ruzicka et al., 1980) of rat neoplasias. According to the concept of Druckrey and Raabe (1952), an advantage in terms of better targeting and higher therapeutic ratio is to be obtained when a cytostatic agent binds more selectively to tumour than to normal cells. In this study we investigated the effects of the nitrosourea derivative 2-chloroethylnitrosocarbamoyl-L-alanine (CNC-L-ala) linked to oestradiol (E2) or dihydrotestosterone (DHT) in terms of antineoplastic activity as well as receptor kinetics in MNU-induced receptor positive rat mammary carcinoma. Material and methods ChemicalsCrystalline N-methyl-N-nitrosourea (MNU) (20/80, v/v)were synthesised by Prof. Dr G. Eisenbrand. The structures of these compounds are shown in Figure 1. CNC-L-ala, CNC-L-ala-E2 and CNC-L-ala-DHT were dissolved at 5% in DMSO.Animals and tumour induction Virgin female Sprague-Dawley (SD) rats (Institut fur Versuchtierkunde, Hannover, FRG) were induced with MNU and tumour bearing rats were treated as described by Berger et al. (1986). The tumours were removed under slight ether anaesthesia, shock-frozen in liquid nitrogen and then stored at -60°C for later hormone receptor determination.

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Androgen-linked alkylating agents: biological activity in methylnitrosourea-induced rat mammary carcinoma

Brix

Berger

Schneider

et al. 1990

J Cancer Res Clin Oncol

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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-alpha-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.

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An oestradiol-linked nitrosourea and site-directed chemotherapy in mammary carcinoma

Cited by 7 publications

References 7 publications

A Critical Appraisal of the Evolution ofN-Nitrosoureas as Anticancer Drugs

A Critical Appraisal of the Evolution ofN-Nitrosoureas as Anticancer Drugs

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

Androgen-linked alkylating agents: biological activity in methylnitrosourea-induced rat mammary carcinoma

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