2. 3 In the
preclinical phase, NAMI-A showed a significant effect on the metastatic
process, whereas KP1019 showed activity against human tumors of colon cancer
and multiple primary transplants. 20

 

KP1019 or FFC14A?Fig.2?, Indazolium
trans-tetrachlorobis(1H-indazole)ruthenate(III) is the second ruthenium-based
anticancer agent developed after NAMI-A developed during the clinical trial
phase. An important step in the mode of action of KP1019 is thought to be a
binding to a serum protein transporter and is transported into the cell by a
transferrin pathway. In addition, by reducing the selective activation of the
tumor may contribute to the low side effects observed in vivo studies. Cell
apoptosis was induced by non-toxic levels through the mitochondrial pathway.
These features distinguish it from established platinum anticancer drugs and
indicate 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 vivo
studies, which can not be successfully treated with cisplatin, and only very
low acquired resistance rates are obtained. KP1019 is suitable
for Lewis lung cancer and primary rectal cancer. Studies have shown that nearly
50 kinds of primary rectal tumors in the treatment of KP1019 can have 80% of
the treatment efficiency, while at the dose of treatment, KP1019 side effects
are very small, in vivo tolerance is also very good,in first clinical stage the
test also has no side effects. 11

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KP1019 is a new
drug effect of tumor suppressor drugs, and platinum drugs are different. It may
involve the accumulation of transferrin receptors in the expression of transferrin
receptors (overexpression) in tumor cells, subsequent reduction into RuII
substances, reaction with DNA, and induction of apoptosis through endogenous
mitochondrial pathways.

 

KP1019 activity is
better than the standard drug 5-fluorouracil in rat colorectal cancer
experimental therapy, which is a kind of human colorectal cancer is very
similar to the tumor model. In this colorectal cancer model, KP1019 produces
approximately one-third of the complete remission of the tumor and therefore
has considerable potential to improve the adverse outcome of conventional
chemotherapy in this common disease. Experiments in a broader tumor are
recommended by experiments in freshly transplanted human tumor samples,
including experiments with anti-standard antineoplastic agents.

 

KP1019 has a very
good tolerance at the therapeutic dose of the test animal, and the slight
effect 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, sodium
trans-tetrachloridobis(1H-indazole)ruthenate(III)) ?Fig 3?and KP1019 (indazolium
trans-tetrachloridobis(1H-indazole)ruthenate(III))  have a high tumour targeting potential based
(1) their strong binding to serum proteins such as albumin
and transferrin, and (2) activation in a reducible tumor environment. 20

Fig 3 NKP-1339
20

 

 

2. 5 Based on the
theory of “activation and reduction”, the mode of action of KP1019
and NKP-1339 appears to be closely related to its redox chemistry(Fig

4) 21
Although Ru has been detected in the nucleus and combined with the DNA of the
extracted cancer cells, there is growing evidence that the anticancer activity
of KP1019 is not primarily based on direct DNA damage.

 

 

However, combine with
DNA, ruthenium compounds and intracellular proteins have been studied less.
Recent studies on intracellular protein binding patterns of KP1019 and NKP-1339
in the cytoplasm of cancer cells have shown that Ru binding can be detected
primarily in two major classes of protein components: protein aggregates /
complexes> 700 kDa and low molecular weight weight proteins ) <40kDa. It is noteworthy that this intracellular drug binding pattern of KP1019 / NKP-1339 is strongly different from the intracellular drug binding pattern of cells exposed to cisplatin.22 In addition to direct biomolecule damage 

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