Antitumour activity of miltefosine alone and after combination with platinum complexes on MXT mouse mammary carcinoma models

Miltefosine, an alkylphosphocholine structurally related to alkyllysophospholipids showed highly selective antitumour activity against the hormone-sensitive variant of the s.c. transplantable MXT mouse mammary adenocarcinoma, the ovary-dependent MXT (M3.2), whereas it was inactive against the hormone-insensitive MXT (M3.2) OVEX variant. A dose of 32 mg/kg miltefosine p.o. daily for 5 weeks was well tolerated. Histopathological evaluation gave no signs of gastroenteral toxicity. After therapy the microarchitecture of the MXT (M3.2) tumours changed from that of a moderately differentiated adenocarcinoma to that of an anaplastic mammary carcinoma. A dose of 16 mg/kg miltefosine p.o. daily, though in effective per se, enhanced the antitumour activity of suboptimal i.p. doses of cisplatin and the hormone-like platinum analogue meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl) ethylenediamine]dichloroplatinum(II). Furthermore, it was shown, that miltefosine exhibited no (anti)hormonal properties. However, the mechanism of action of miltefosine remains unclear

Tumor inhibiting [1,2-bis(fluorophenyl)ethylenediamine]platinum(II) complexes, III: Evaluation of the mammary tumor inhibiting properties

Diastereomeric diaqua[1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) sulfates and nitrates produce a strong inhibition of the hormone-dependent MXT-M 3.2 mammary carcinoma of the B6D2F1 mouse. Besides an interference in the DNA synthesis in analogy to cisplatin a lowering of the estrogen level due to an interference in steroid biosynthesis is suggested as the mode of action. In contrast to the R,R/S,S configurated diaqua[1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) salts the corresponding R,S configurated compounds are also markedly active on the hormone-independent MXT-Ovex mammary carcinoma of the B6D2F1 mouse

Tumor-inhibiting [1,2-bis(fluorophenyl)ethylenediamine]platinum(II) complexes. V. Synthesis and evaluation of enantiomeric [1,2-bis-(4-fluorophenyl)ethylenediamine]dichloroplatinum(II) complexes

The enantiomeric [1,2-bis(4-fluorophenyl)ethylenediamine]dichloroplatinum(II) complexes were synthesized and tested on the hormone-sensitive human MCF7 breast cancer cell line and on the P388 leukemia of the mouse. They showed a strong and comparable activity on both tumor models

[1,2-Bis(2-hydroxyphenyl)ethylenediamine]dichloroplatinum(II), a new compound for the therapy of ovarian cancer. III. Detailed evaluation of the antitumor activity of the enantiomeric complexes on the human NIH:OVCAR-3 ovarian cancer cell line

The stereoisomeric [1,2-bis(2-hydroxyphenyl)ethylenediamine]dichloroplatinum(II) complexes were thoroughly tested on the cisplatin-resistant human NIH:OVCAR-3 ovarian cancer cell line. The racemate and its enantiomers produced cytocidal effects at a concentration of 2.5 microM (incubation time 256 h). The meso form, however, was merely cytostatically active. Differences between the enantiomers became evident after a short drug incubation time (1 h) followed by an incubation in drug-free medium (243 h). The S,S-configurated enantiomer (-)-3-PtCl2 proved to be the most active compound. To achieve cytocidal effects concentrations of 2.5-5.0 microM and incubation times of about 3 h were necessary for (-)-3-PtCl2. This compound is also sufficiently stable under test conditions as shown by the preincubation in cell-free medium for 3 h. These results and the augmentation of its antitumor activity by buthionine sulfoximine recommend the further preclinical development of (-)-3-PtCl2 for clinical use

[1,2-Bis(2-hydroxyphenyl)ethylenediamine]dichloroplatinum(II), a new compound for the therapy of ovarian cancer. II. Synthesis and preliminary testing of the enantiomeric complexes

The enantiomeric [1,2-bis(2-hydroxyphenyl)-ethylenediamine]dichloroplatinum(II) complexes were synthesized and their configuration assessed. A preliminary test in the cisplatin-resistant human NIH:OVCAR-3 ovarian cancer cell line, which was previously characterized by its sensitivity against several therapeutically used drugs, showed that both enantiomers produce cytocidal effects in a concentration of 2.5 microM. A difference between the enantiomers became evident from the faster onset of cytocidal activity of the S,S-configurated compound

Pharmacokinetics and tissue distribution of bovine testicular hyaluronidase and vinblastine in mice: an attempt to optimize the mode of adjuvant hyaluronidase administration in cancer chemotherapy

The influence of the route of administration (i.v., i.p. and s.c.) on pharmacokinetics and tissue distribution of bovine testicular hyaluronidase and vinblastine was studied in mice (plasma, skeletal muscle, liver, kidney and human melanoma). After i.v. injection, hyaluronidase was accumulated in liver and kidney, whereas i.p. and s.c. administration led to almost equal distribution in plasma, muscle, liver and kidney. In melanoma, the highest levels of hyaluronidase were found after s.c. injection of the enzyme close to the tumor. Hyaluronidase s.c. increased the intratumoral concentration of s.c. co-administered vinblastine most efficiently, making local simultaneous application as in interstitial chemotherapy most promising

Computerized determination of growth kinetic curves and doubling times from cells in microculture

In this paper we describe the microcomputer-aided determination of cell proliferation kinetics and doubling times utilizing a crystal violet assay and a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay in microtitration plates. The analysis of spectrophotometric data provides the doubling times at any time of incubation. Plots of doubling time versus time of incubation give reproducible information on the exact duration of the logarithmic growth phase. This method is applicable to anchorage-dependent as well as anchorage-independent cells when colorimetric or fluorometric data are accessible

Does [meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine] dichloroplatinum(II) act as an immune response modifier? IV. Inhibition of the proliferation-increasing effect of progressively growing MXT-M-3,2 breast cancer on phagocytes by the title compound

In female B6D2F1 mice bearing an MXT-M-3,2 breast cancer graft the level of the phagocytic cells (e.g. of granulocytes and macrophages in the spleen and of granulocytes and monocytes in the blood) is significantly elevated. The positive correlation between the number of the phagocytic cells and the weight of the tumor indicates that the MXT-M-3,2 breast cancer promotes myelopoiesis, presumably by secretion of hematopoietic growth factors like GM-CSF. This process can be described for each phagocyte type by a regression equation. Due to its hormonal potency [meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine] dichloroplatinum(II) (meso-1-PtCl2) can reduce the excessive numbers of the granulocytes and macrophages, which seem to be responsible for the progressive growth of the MXT-M-3,2 breast cancer. This process leads to an interruption of the vicious circle of mutual growth stimulation of breast cancer cells and these phagocytes. The target of meso-1-PtCl2 is the estrogen receptor (ER) of the breast cancer cell. The interaction between meso-1-PtCl2 and the ER presumably results in a diminished secretion of hematopoietic growth factors and hence in a decline of the number of phagocytic cells. Meso-1-PtCl2 does not inhibit the proliferation of tumor cells by direct interaction with their DNA, as is described for platinum complexes like cDDP. In its mode of action the equipotent, breast cancer inhibiting drug cDDP differs from meso-1-PtCl2. This is obvious from the fact that in cDDP--but not in meso-1-PtCl2-treated, tumor bearing mice the number of granulocytes and macrophages does not markedly deviate from that in untreated control mice with tumors of the same weight. The drug cDDP probably does not interfere with the mechanism of the secretion of hematopoietic growth factors. The reduction of the number of tumor cells by cDDP leads to a decline of the number of phagocytic cells in accordance with the respective regression equations. In contrast to meso-1-PtCl2 and cDDP, ovariectomy causes elevated phagocyte numbers, probably due to the strongly reduced estrogen level. The studies described in this publication indicate that the anti-breast cancer activity of meso-1-PtCl2 is caused by a decimation of phagocytes and with this by an abolition of the tumor promoting effect. Furthermore, a restoration of the natural immunosurveillance seems to be of importance