DNA synthesis

In comparison to nedaplatin, CDDP, or 5-FU monotherapy, the sequential administration of 5-FU before nedaplatin or CDDP (FN or FC therapy) results in synergistically enhanced inhibition of tumour growth and prolonged survival.[4] When Nedaplatin and Gemcitabine are administered together, the Ma44 tumor model exhibits a synergistically enhanced inhibition of tumor growth. When administered toward the end of the therapy, nedaplatin plus gemcitabine is also effective against Ma44 cells, a model for advanced disease. The NCI-H460 tumor model also demonstrates a strong enhancement of growth inhibition by neoplatin when combined with gemcitabine.[5]

An assay for regrowth is used to measure the antitumor activity of the drug treatments, which include the inhibition of cell proliferation (including that of human SCLC cell line SBC-3 and human NSCLC cell line PC-14). To put it briefly, cells are treated with drugs alone or in combination for six days at 37°C in a 100% humidity and 5% CO2 environment. After that, the cells are pipetted six to eight times, or nearly all of them become single cells, and they are counted using a counter. Plotting the percentage of surviving cells (the unaffected cell fraction, fu) against drug concentration yields concentration-effect curves for each drug. To calculate the treated:control cultures' cell proliferation ratio (T:C%), use the formula below: [(the number of treated cells on day 6)/(the number of treated cells on day 0)]/[(the number of control cells on day 6)/(the number of control cells on day 0)] × 100%. The drug concentration needed to cause a 50% decrease in the number of cells is known as the IC50. For each, four or five separate experiments are conducted. In order to assess the impact of the drug treatment schedule on the combination's effect, the cells are treated for three hours either sequentially—first with Nedaplatin and then with irinotecan (Nedaplatin→irinotecan) or simultaneously with both drugs. Cells are exposed to the first drug for three hours during the sequential exposure treatment, then they are immediately exposed to the second drug for three hours after being ished in fresh medium once. Up until assessment, the treated cells are cultivated in a drug-free medium.

Tumor-bearing athymic BALB/c nude mice with Ma44 or NCI-H460 cells
10 mg/kg or 20 mg/kg
Administered via i.v.

Absorption, Distribution and Excretion
Most of the platinum from nedaplatin is eliminated in the urine (59.6%).
The volume of distribution of free platinum is 12.0 L.
Clearance of the free platinum is 4.47 L/h.

Protein Binding
Approximately 50% of the platinum from nedaplatin appears to be bound to human plasma proteins.

[1]. Cancer Chemother Pharmacol . 1997;39(6):493-7.

[2]. Dalton Trans . 2010 Sep 21;39(35):8113-27.

[3]. Clin Cancer Res . 2001 Jan;7(1):202-9.

[4]. Eur J Cancer . 1998 Oct;34(11):1796-801.

[5]. Jpn J Cancer Res . 2001 Jan;92(1):51-8.

[6]. Cancer Res . 2014 Jul 15;74(14):3913-22.

Nedaplatin is a second generation platinum analog. It is less nephrotoxic than [DB00515] but has proven equally effective. It was approved for use in Japan in 1995.
Nedaplatin is a second-generation cisplatin analogue with antineoplastic activity. Containing a novel ring structure in which glycolate is bound to the platinum by a bidentate ligand, nedaplatin forms reactive platinum complexes that bind to nucelophillic groups in DNA, resulting in intrastrand and interstrand DNA cross-links, apoptosis and cell death. This agent appears to be less nephrotoxic and neurotoxic compared to both cisplatin and carboplatin.

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Drug Indication
Used in the treatment of non-small cell lung cancer, small cell lung cancer, oesophygeal cancer, and head and neck cancers.

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Mechanism of Action
As a platinum analog, nedaplatin likely works similarly to [DB00515] on which the following mechanistic description is based. Once it has entered the cell it is hydrolyzed to its active form which complexes with water molecules. This form binds to to nucleophiles in the cytoplasm such as glutathione and other cyteine rich proteins resulting in an overall increase in oxidative stress as the cell loses antioxidant proteins. It also binds to purine nucleotides in the DNA. The active form allows for two binding interactions to form cross-links between these nucleotides. High mobility group proteins-1 and -2 induce apoptosis in response to guanine cross-links and their binding serves to shield the cross-linked DNA from repair mechanisms. The mismatch repair (MMR) protein complex also recognizes the distortion caused by platinum complexes and attempts to repair the DNA. This results in single strand breaks when the MMR complex attempts to remove the platinum cross-link. The MMR complex induces apoptosis after the repair attempt has failed. The single strand break in DNA makes it easier to form lethal double strand breaks with radiation treatment thus creating the radiosensitizing effect of nedaplatin.

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Pharmacodynamics
Nedaplatin damages DNA and induces cell death in cancer cells. It also functions as a radiosensitizer, increasing the susceptibility of the affected cells to radiation therapy.

C2H8N2O3PT

303.17

303.018

C, 7.98; H, 2.01; N, 9.30; O, 15.94; Pt, 64.78

95734-82-0

72120

Light yellow to yellow solid powder

265.6ºC at 760 mmHg

128.7ºC

0.12

4

5

0

8

50.5

0

[Pt+2].O([H])C([H])([H])C(=O)O[H].[N-]([H])[H].[N-]([H])[H]

ZAXCMPAWRCMABN-UHFFFAOYSA-N

InChI=1S/C2H4O3.2H3N.Pt/c3-1-2(4)5;;;/h3H,1H2,(H,4,5);2*1H3;

azane;2-hydroxyacetic acid;platinum

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product is not stable in solution, please use freshly prepared working solution for optimal results.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: 7.14 mg/mL (23.55 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)