Explanation of the mechanism of carcinogenesis and syntheses of anticancer agents with high selectivity

Abstract

In 1979, the mechanism of chemical carcinogenesis, a challenging and difficult scientific problem pending for a number of years, was explained by Dai Qianhuan. The mechanism named di-region theory predicted that a carcinogen always metabolizes to form a special bi-functional alkylating agent. This agent induces cross-linkages between the complementary base pairs in DNA and switches on initial mutageneses in genomes including point and frameshift mutations. This, in turn, induces further deep mutageneses including the production of various chimeric chromosomes, deletions and other aberrations found in genomes. In the end this initiates carcinogenesis of the whole cell through the reverse transcription mechanism after a lengthy incubation period. Recently, this laboratory has verified that physical carcinogenesis, including the oncogenesis induced by radiation and asbestos as well as the carcinogenesis induced by endogenous factors such as estrogen or diethyl-stilbestrol switch on carcinogenesis by inducing the formation of cross-linkages between the complementary base pairs in DNA.

Di-region theory has now been supported by many experimental observations such as mutational spectra of various carcinogens. The potential for carcinogenesis, teratogenesis, sterility and mutagenesis lumped together as genetic toxicity appears to originate almost uniformly from the cross-linking between complementary bases, i.e. malignant cross-linking, which is in accordance with di-region theory. Other forms of cross-linking between non-complementary bases, benign cross-linkings, show bi-functional alkylation anticancer activity but lack genetic toxicity. The predictable design and synthesis of a high selectivity anticancer agent with high efficacy and low genetic toxicity, a goal long pursued in cancer chemotherapy, have been realized for the first time in this laboratory by inhibiting malignant and heightening benign cross-linking using the principles of di-region theory. A series of patented new anticancer platinum complexes called di-regioplatins, based on the above predetermined design, have been reported. In these cancer cell kill rates, tumor-inhibition rates and the ultimate life-span for two mouse carcinoma models using several com-pounds of cis-di-substituted-benzylaminodihaloplatinum (II) are notably higher than those of cisplatin, but their toxicities all are much lower than cisplatin. Based on a predictive design using di-region theory and group theory, a new anticancer complex, cis-diammine-cyclopentane-1,1-dicarboxylato-platinum (II) called minoplatin, has been synthesized in this laboratory by making the minimal structural revision of adding an CH₂ unit on the four-member ring of carboplatin.

The water solubility of minoplatin is almost double that of carboplatin, yet its lipid solubility is much higher than carboplatin. Animal acute toxicity of minoplatin is only half that of carboplatin, and the curative effect of minoplatin in a rapid growing animal tumor model of the ascites-type is remarkably higher than that of carboplatin. Genetic toxicity of minoplatin as measured by reverse mutagenesis with the TA 102 strain is only 1/200 of cisplatin and 1/10 of carboplatin. Minoplatin, as opposed to cisplatin, shows no teratogenesis to the offspring of pregnant female mice. Additionally, some recent empirical research results on anticancer platinum complexes have been explained by the di-region theory, and comments from the perspective of predicting the selectivity of anticancer agents have been presented. We anticipate that future clinical testing will demonstrate that minoplatin and di-regioplatins are the first examples in a class consisting of highly selective, low toxicity, and tailored second generation anticancer agents.