2. 3 In thepreclinical phase, NAMI-A showed a significant effect on the metastaticprocess, whereas KP1019 showed activity against human tumors of colon cancerand multiple primary transplants. 20  KP1019 or FFC14A?Fig.2?, Indazoliumtrans-tetrachlorobis(1H-indazole)ruthenate(III) is the second ruthenium-basedanticancer agent developed after NAMI-A developed during the clinical trialphase. An important step in the mode of action of KP1019 is thought to be abinding to a serum protein transporter and is transported into the cell by atransferrin pathway. In addition, by reducing the selective activation of thetumor may contribute to the low side effects observed in vivo studies.

Cellapoptosis was induced by non-toxic levels through the mitochondrial pathway.These features distinguish it from established platinum anticancer drugs andindicate that different types of cancer may be treated with this drug. In fact,activity against certain types of tumors has been observed in vitro and in vivostudies, which can not be successfully treated with cisplatin, and only verylow acquired resistance rates are obtained. KP1019 is suitablefor Lewis lung cancer and primary rectal cancer. Studies have shown that nearly50 kinds of primary rectal tumors in the treatment of KP1019 can have 80% ofthe treatment efficiency, while at the dose of treatment, KP1019 side effectsare very small, in vivo tolerance is also very good,in first clinical stage thetest also has no side effects. 11 KP1019 is a newdrug effect of tumor suppressor drugs, and platinum drugs are different. It mayinvolve the accumulation of transferrin receptors in the expression of transferrinreceptors (overexpression) in tumor cells, subsequent reduction into RuIIsubstances, reaction with DNA, and induction of apoptosis through endogenousmitochondrial pathways.

 KP1019 activity isbetter than the standard drug 5-fluorouracil in rat colorectal cancerexperimental therapy, which is a kind of human colorectal cancer is verysimilar to the tumor model. In this colorectal cancer model, KP1019 producesapproximately one-third of the complete remission of the tumor and thereforehas considerable potential to improve the adverse outcome of conventionalchemotherapy in this common disease. Experiments in a broader tumor arerecommended by experiments in freshly transplanted human tumor samples,including experiments with anti-standard antineoplastic agents. KP1019 has a verygood tolerance at the therapeutic dose of the test animal, and the slighteffect of erythropoiesis is the only major side effect in the applicable dose. 11 Fig.2  KP1019 20  2.

4 Both NKP-1339(the sodium salt analogue of KP1019, sodiumtrans-tetrachloridobis(1H-indazole)ruthenate(III)) ?Fig 3?and KP1019 (indazoliumtrans-tetrachloridobis(1H-indazole)ruthenate(III))  have a high tumour targeting potential based(1) their strong binding to serum proteins such as albuminand transferrin, and (2) activation in a reducible tumor environment. 20Fig 3 NKP-133920  2. 5 Based on thetheory of “activation and reduction”, the mode of action of KP1019and NKP-1339 appears to be closely related to its redox chemistry(Fig4) 21Although Ru has been detected in the nucleus and combined with the DNA of theextracted cancer cells, there is growing evidence that the anticancer activityof KP1019 is not primarily based on direct DNA damage.  However, combine withDNA, ruthenium compounds and intracellular proteins have been studied less.Recent studies on intracellular protein binding patterns of KP1019 and NKP-1339in the cytoplasm of cancer cells have shown that Ru binding can be detectedprimarily in two major classes of protein components: protein aggregates /complexes> 700 kDa and low molecular weight weight proteins ) <40kDa. Itis noteworthy that this intracellular drug binding pattern of KP1019 / NKP-1339is strongly different from the intracellular drug binding pattern of cellsexposed to cisplatin.22 In addition to directbiomolecule damage 


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