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

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

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

Different response of murine and human mammary tumour models to a series of diastereoisomeric [1,2-bis(difluorophenyl) ethylenediamine]dichloroplatinum(II) complexes

A series of isomeric [1,2-bis(difluorophenyl) ethylenediamine]dichloroplatinum(II) complexes and cisplatin were tested on the P388 leukemia and on the murine hormone-independent MXT (M3.2) OVEX and the ovarian-hormone-dependent MXT (M3.2) mammary carcinoma for evaluating antineoplastic activity against breast cancer in vivo. Although these results were heterogeneous, a trend to the 2,6-difluorosubstituted compound as the most active platinum complex was observed. For the development of a large-scale in vitro screening method on human breast cancer cell lines, cell number, [3H]thymidine incorporation, and crystal violet staining were evaluated as parameters for end-point determination. Chemosensitivity testing on the human breast cancer cell lines MDA-MB-231 and MCF-7 unambiguously identified [1,2-bis(2,4-difluorophenyl)ethylenediamine]dichloroplatinum(II) as the complex with the highest activity in the crystal violet micro-assay. In equimolar concentration this compound was superior to cisplatin on both cell lines. The analysis of the conflicting results of this study indicates that murine mammary carcinomas are most probably unrealistic and inappropriate models for the screening of cytotoxic platinum complexes with potential activity on human breast cancer

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

Quantitation of hyaluronidases by the Morgan-Elson reaction: comparison of the enzyme activities in the plasma of tumor patients and healthy volunteers

The Morgan-Elson reaction, a method for the detn. of hyaluronidase activity, was optimized for the quantitation of the enzyme in biol. material. Based on HPLC and spectrometric (UV-Vis, LC-MS) studies, the structure of the red-colored product (mesomeric forms of N3-protonated 3-acetylimino-2-(4-dimethylaminophenyl)methylidene-5-(1,2-dihydroxyethyl)furane) formed by condensation of chromogen III with p-dimethylaminobenzaldehyde is proposed. Activities corresponding to ³0.1 IU of endogenous and therapeutically administered hyaluronidase can be detected in 50 ml samples. Application of the method for the detn. of the enzyme in plasma of tumor patients revealed no difference in activity levels, interindividual variability and pH profile compared to healthy volunteers