Effect of stereoisomers related to ICRF-159 on metastasis of B16 melanoma

Abstract

Summary.-The antitumour effects of ICRF-159 and related analogues were evaluated using the B16 melanoma. Treatment of mice with ICRF-159 inhibited tumour growth, while each of the analogues, trans-4,41-(1,2-cyclopropandiyl) bis (2,6-piperazinedione) (trans-5), and cis-4,41-(1,2-cyclopropandiyl) bis (2,6-piperazinedione) (cis-7) independently accelerated primary tumour growth. Pretreatment of B16 melanoma cultures either with ICRF-159 or the analogue cis-7 decreased the yield of lung-colonies following i.v. injection of tumour cells. In contrast, pretreatment of tumour cells with the trans-5 analogue led to an increase in lung colonies. The effect on colony formation in vitro of these analogues correlated with increased growth in vivo, and not with lung colony formation.PREVIOUS REPORTS from these laboratories have shown that ICRF-159 and analogue trans-5 stimulated the growth of a hamster adenocarcinoma of the lung, whereas ICRF-159 and Analogue cis-7 had no effect on primary tumour growth. The results also suggested that Analogue cis-7 reduced metastasis of this tumour model whilst trans-5 stimulated it (Witiak et al., 1978). Since ICRF-159 is active against a variety of tumours (Adamson, 1975;Atherton, 1975), and has been reported to inhibit metastasis to the lung of subcutaneously growing Lewis lung carcinoma (LeServe & Hellmann, 1972;Salsbury et al., 1970), this stereochemical effect on tumour growth and metastasis is particularly significant. As a prerequisite to mechanism studies we have re-examined the activity of these compounds, using the syngeneic B 16-Fl and F 10 melanoma in C57BL/6 mice (Fidler & Nicholson, 1976 Fig. 1) were studied to throw light on the specificity of the apparent stereoselective effect. The results described in this article are compared to those previously reported by Lazo et al. (1978), who observed that ICRF-159 treatment of B16 melanoma cells in culture significantly increased their lung-colony formation in vivo. MATERIALS AND METHODSAnimals.-Male, C57BL/6J mice were obtained from the Jackson Laboratory, Bar Harbor, Maine, when 5 weeks old. The animals were housed 20 per cage and given food and water ad libitum. Mice were used when 8-12 weeks of age.Tumours. The B16-Fl and B16-FIO melanoma tumour cells were kindly provided by Dr Isiah J. Fidler. The B16-F1 cell line forms few lung colonies when injected i.v., whereas (orre.;Pondence to: Bruce S. Zvilling, The

The evolution of a cardioprotective antimetastatic and antitumor drug: An international adventure

“…In contrast, the trans compound (10) stimulated both the lung metastasis and the primary tumor growth. Similar stereoselective effects of isomers 10 and 11 were also observed on lung metastasis of B16-F10 melanoma in mice (27). Pretreatment of B16-F10 cell lines for 24 h with trans-10 at 2 /rM and 20 pM concentrations resulted in an increase in lung melanoma colony formation.…”

Adriamycin analogs. Rationale, synthesis, and preliminary antitumor evaluation of highly active DNA-nonbinding N-(trifluoroacetyl)adriamycin 14-O-hemiester derivatives

“…Reaction of 350 mg (0.48 mmol) of 7 with sebacic acid monosodium salt (1.8 g) in 400 mL of acetone containing 3 mL of water at reflux for 14 h, followed by isolation and purification as before, afforded 16 (242 mg, 63%): mp 108-112 °C dec; Chemical, biochemical, and pharmacological properties of antitumor bis(dioxopiperazines) recently have been reviewed.2 Cyclic analogues 4-9 of 1 and 2 exhibited stereoselective effects in various tumor models. [3][4][5][6] In the solid state a cis "face to face" conformation of the dioxopiperazine rings were observed in antimetastatic racemic 2 and cis-5.7,8 However, such a conformation seems not to be essential for activity since tricyclic bis(dioxopiperazine) trans-6 exhibited antimetastatic properties in the B16-F10 melanoma model.5,9…”

“…Although such compounds are predictably unstable and undergo hydrolysis to the parent dioxopiperazines, morpholinomethyl-N groups may impart antineoplastic properties to a molecule owing to possible alkylating activities not unlike those proposed11 for certain hydroxymethyl-N metabolites of therapeutically useful drugs. Comparative analysis of morpholinomethyl derivatives 8 and 9 with the respective parent imides 6 and 7 in a postoperative Lewis Lung (LL) carcinoma model revealed morpholinomethyl cis-syn-trans isomer 9 to be more effective as an inhibitor of metastasis than the other three analogues (6)(7)(8).12 Additionally, the order of decreasing activity was 9 > 8 > 7 > 6 when assessed in terms of survival or antimetastatic data. The increased activity observed for the morpholinomethyl derivatives over their respective parents was attributed12 either to increased solubility and drug delivery (prodrug) or to an intrinsic antitumor activity of the morpholinomethyl-N functionality possibly reflecting macromolecular alkylation.…”

“…In the search for such analogues, these laboratories have been responsible for the conceptualization, synthesis, preclinical development, and clinical introduction of the novel analogue AT-(trifluoroacetyl)adriamycin 14-valerate (AD 32, 3). 6,7 In marked contrast to 1 and 2, 3 does not bind with double-helical DNA.8,9 Consequently, the range of biochemical and biological properties exhibited by 3 in in vitro and in vivo systems, often with effects superior to those of 1 under similar conditions,10"21 cannot be explained (3) Blum, R. H.; Carter, S. K. Ann. Intern.…”