Meet Cisplatin

Cancer is widely recognized as one of the most dangerous diseases in the world. The term cancer usually refers to a malignant tumor. In simple terms, cancer or malignant tumors are defined as body cells that reproduce uncontrollably where these cells continue to grow even though our bodies don't need them anymore. These cancer cells can then spread to other areas of the body that are different from their origin. When the cancer has spread widely, it will be very difficult to cure. For that special treatment must be required.

In general, there are two factors that cause cancer according to the World Health Organization (WHO), namely first, environmental factors that play a role in 80-90% of cancer, which include environmental factors including cigarette smoke (40%), food consumption (25- 30%), and the air around the residence (10%) and the second factor is genetic factors and maybe a virus of 10-20%. One way to treat cancer is chemotherapy, which is therapy using drugs to destroy cancer cells. Some drugs that are often used for chemotherapy are taxol, cisplatin, and bleomycin. Especially for cisplatin in modern medicine today it has been proven to be very effective for treating various types of cancer and is most often used in cancer chemotherapy.

Cisplatin or cisplatinum or cis diamminedichloroplatinum(II) is a platinum-based cancer chemotherapy drug. Basically, thousands of compounds have been synthesized as platinum derivatives that have shown antitumor/anticancer properties. But only 28 of them have been clinically tested and only 2 are highly active namely cisplatin itself and carboplatin.

Table 1. Clinical Status and Toxicity Limit Doses of Several Platinum-Based Drugs

Platinum drug	Dosage (mg/m 2	Toxicity Limit	Clinical Status
Cisplatin	60-120	Nephrotoxicity	Accepted worldwide
Carboplatin	Up to 900	Myelosuppression	Accepted worldwide
Oxiliplatin	200	neuropathy	Accepted in France
Nedaplatin	100-200	Myelosuppression	Accepted in Japan
JM-216	400	Myelosuppression	Rejected in phase (II)
L-NDDP	400	Neutropenia, Thrombocytopenia	Phase (II)
AMD-473	TBD	TBD	Phase (I)
BBR3464	>1,1	Neutropenia, nausea	Phase (II)
Ormaplatin	90	Unpredictable, peripheral, neurotoxicity	Rejected

Cisplatin

The chemical structure of cisplatin is cis -PtCl 2 (NH 3 ) 2 . This compound was first discovered by M. Peyrone (1845) derived from Peyrone's salt and its structure was determined later by Alfred Werner (1893). This cisplatin compound was synthesized by exploiting the trans effect between potassium tetrachloroplatinate(II), K 2 PtCl 4 and amine ligand (NH 3). The chemical structure that is formed is in accordance with the classical structural requirements to make platinum metal have anti-cancer activity, namely (1) Pt oxidation number +2 or +4, (2) The amine ligand must be in the cis position, (3) The total charge of the platinum complex compound must be neutral, (4) The amine ligand (NH3) must have at least one remaining NH group, and finally (5) The leaving group must be an anion with medium bond strength such as a chloride or carboxylic derivative.

Cisplatin works as an anti-cancer by attaching itself to the DNA ( deoxyribonucleic acid ) of cancer cells and preventing their growth.

Figure-1: Forms of bonds between Visplatin and DNA

Basically, cisplatin in general is not a relatively reactive compound and easily reacts directly with all types of active molecules in biological systems, including the bases of DNA. But when this compound is dissolved in water, the chloro ligands in cisplatin are replaced one by one by water (aqua) ligands through a hydrolysis reaction. Furthermore, the Pt-OH2 bond contained in the monoaquaplatina and diaquaplatina complexes that are formed will be much more reactive, so that the complex will more easily react with nitrogen atom donor ligands in the DNA base.

Cisplatin and Cancer Treatment

Today cisplatin is widely used to treat various cancers, especially very effective for testicular cancer and when combined with other drugs it will work very effectively in treating ovarian cancer, bladder cancer, lung cancer, head and neck cancer. The combination of cisplatin may include combination with radiotherapy or with certain drugs such as pacliataxel, aphidicolin and hydroxyurea or 5-fluorouracil.

The combination of cisplatin, vinblastine and bleomycin will cure 90% of testicular cancer. Meanwhile, the combination with cyclohosphoramide, dioxorubicin and hexamethylmelamine will be able to increase the survival of patients with advanced ovarian cancer. For lung cancer or non-small cell lung cancer (NSCLC), four combinations of platinum can be used, namely cisplatin/paclitaxel, gemcitabine/cisplatin, cisplatin/docetaxel and carboplatin/paclitaxel. In addition, the addition of avastin to the cisplatin/gemcitabine combination will be very effective in prolonging the survival of NSCLC patients by up to 20-30%. For other types of cancer, it also shows sensitivity to cisplatin at several levels as shown in table 2.

Table 2. Biological Activity of Cisplatin Against Various Types of Cancer

Type of Cancer	sensitivity
Testicular	curable
Ovarian	sensitive
Head and neck	Responsive
Bladder	Responsive
Nape, prostate, esophagus	resistance
NSCL (Non-Small Cell Lung)	Shows activity
Osterogenic	Shows activity
Hodgkins Lymphoma	Shows activity
Melanoma	Limited activity
Chest/Breast	Limited activity

Cisplatin Side Effects and Drug Delivery

Cisplatin, like other common drugs used for chemotherapy, also has severe side effects. This includes very chronic and dangerous neprotoxicity, but this neprotoxicity can be minimized by hydration of the patient and using mannitol as a diuretic. In addition, other side effects are neurotoxicity, nausea, vomiting, bone marrow poisoning, hair loss (alopecia), and decreased immunity. But fortunately for hair loss and decreased immunity, it will generally return to normal after treatment.

Today, to reduce the side effects of using cisplatin chemotherapy, the solution is to use drug delivery. One way is to use a nanohorn. Nanohorn is a type of nanotube which has one end of a cylinder that is tapered and closed like a horn. This nanohorn measures 100 nanometers in which there is already cisplatin measuring 1-2 nanometers. This nanohorn is safe for the body because it comes from the element carbon.

Figure-2 : Electron Microscopy Photo of : (a) A group of nanohorns containing cisplatin (black spots) in their cavity and (b) One cisplatin grain that is in a cavity of a nanohorn.

This nanohorn is an effective drug delivery agent because after being injected into the patient's body, the nanohorn is immediately absorbed by the cancer cells. Thus, the side effects of chemotherapy which can damage other body cells, can be avoided. After the nanohorns have accumulated (collected) in the cancer cells, cisplatin slowly releases and kills the cancer cells.

Closing

Treatment of cancer with cisplatin that has been done so far has given hope for longer health for many cancer sufferers. Although cisplatin has been proven effective in treating cancer, the research and development of cisplatin does not stop there. Various studies that lead to a combination of two drugs between cisplatin and other cancer drug candidates are still being researched by various researchers until now. In addition to therapy using two drugs, it is also possible to combine three drugs at once as therapy for patients with non-small cell lung cancer (NSCLC) which combines cisplatin/gemcitabine plus an anti-angiogenic drug, namely avastin.

Bibliography

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