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.
Schlemmer
R
R
Lehrstuhl für Pharmazeutische Chemie II, Institut für Pharmazie, Universität Regensburg, D-93040 Regensburg, Germany. richard.schlemmer@stud.uni-regensburg.de
Spruss
T
T
Bernhardt
G
G
Schönenberger
H
H
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D005260:Female; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D010586:Phagocytes / Q000187:drug effects* / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D014407:Tumor Cells, Cultured
C407803:(meso-1,2-bis-(2,6-dichloro-4-hydroxyphenyl)ethylenediamine)dichloroplatinum(II); D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds