A new suggestion of the design of rational anticancer therapy: experimental studies in mice.
In attempts to develop a rational anticancer strategy the same homologous tissue in 3 conditions were used side by side as targets: normal epidermis of the mouse back. Tween 60R-provoked benign epidermal hyperplasia, and carcinogen-provoked malignant condition. In contrast to the highest tolerated doses of the cytostatics conventionally used, the dose was stepwise decreased towards the subthreshold level. Then the smallest dose that caused the slightest detectable injury to the malignant cells was employed. The results show that the dose of the cytostatics (colchicine, and vinblastine sulfate) can be reduced to 1/12 if the drug is linked to dimethyl-sulfoxide (DMSO), a compound with unique hydrating and oxido-reducing properties. The cytostatic-DMSO complex acts selectively, sparing the viability of the normal and hyperplastic cells, but at the same time increasing the vulnerability of the malignant cells. The specific target for cytostatic-DMSO complex is the 3-dimensional cytoskeleton (the differentiation organelle) which is deranged in malignant cells. The measure causes a morbid swelling (20-fold, or more) of the cytoplasm which leads to collapse of the cytoskeleton, so that the marginal quantities of the cytostatics can exert their effects in the highly re-hydrated water matrix of the malignant cells. It is, moreover, probable that the doses of the cytostatic in DMSO could be further reduced to 1/100, or even to 1/1,000. The polarization microscopic technique reveals events down to the (sub)-molecular level. The cytological material comprises 930,000 karyokinetic assemblies and 14,522,600 corresponding nucleated non-dividing cells in various cutaneous conditions of 1,860 mice. The conclusions were drawn only when the differences between corresponding parameter pairs were statistically highly significant (P less than 0.001).
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D003078:Colchicine / Q000627:therapeutic use*; D003593:Cytoplasm / Q000187:drug effects; D004121:Dimethyl Sulfoxide; D004305:Dose-Response Relationship, Drug; D004817:Epidermis / Q000187:drug effects / Q000473:pathology; D006965:Hyperplasia; D007365:Intercellular Junctions / Q000187:drug effects; D008854:Microscopy, Electron; D008938:Mitosis / Q000187:drug effects; D009115:Muridae; D009374:Neoplasms, Experimental / Q000188:drug therapy; D014677:Pharmaceutical Vehicles; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014747:Vinblastine / Q000627:therapeutic use*
D014677:Pharmaceutical Vehicles; D014747:Vinblastine; D003078:Colchicine; D004121:Dimethyl Sulfoxide