cisplatin in anticancer drugs

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CISPLATIN IN ANTICANCER DRUGS. Presented By: Imliwati Longkumer Department of Chemistry F.A.C. Mokokchung 1

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Cisplatin is one of the most important anticancer drug for chemotherapy.

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Page 1: Cisplatin in anticancer drugs

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CISPLATIN IN ANTICANCER DRUGS.

Presented By: Imliwati Longkumer

Department of Chemistry F.A.C. Mokokchung

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OUTLINE OF MY PRESENTATION

INTRODUCTION

• Cancer

• Causes of cancer

• Different forms of cancer treatment

CISPLATIN

MECHANISM OF ACTION OF CISPLATIN

SOME 2nd GENERATION PLATINUM BASED ANTICANCER DRUGS

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INTRODUCTIONWhat is cancer?Cancer is a class of diseases in which a group of cells display uncontrolled growth, invasion that intrudes upon and destroys adjacent tissues, and sometimes metastasis, or spreading to other locations in the body via lymph or blood.

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CausesCancers are primarily an environmental disease with 90-95% of cases attributed to environmental factors and 5-10% due to genetics. Environmental, as used by cancer researchers, means any cause that is not genetic. Common environmental factors that contribute to cancer death include: tobacco (25-30%), diet and obesity (30-35%), infections (15-20%), radiations (both ionizing and non ionizing, up to 10%), stress, lack of physical activity, and environmental pollutants.

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DIFFERENT FORMS OF CANCER TREATMENT1. Radiation therapy

2. Chemotherapy

3. Surgery

4. Targeted Therapy

5. Immunotherapy

6. Hyperthermia

7. Stem Cell Transplant.

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Radiation therapy:Radiation therapy (or radiotherapy) is an important technique for shrinking tumors. High energy waves(such as X-ray) are targeted at the cancerous growth. The waves cause damage within the cells, disrupt cellular processes, prevent accurate cell division, and ultimately cause the cells to die. The death of the cells causes the tumor to shrink. One drawback of radiotherapy is that radiation is not specific to cancerous cells and may damage healthy cells as well.

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Chemotherapy:In the most simple sense, is the treatment of an ailment by chemicals especially by killing micro-organisms or cancerous cells. Most commonly, chemotherapy acts by killing cells that divide rapidly, one of the main properties of most cancer cells.

This means that it also harms cells that divide rapidly under normal circumstances. Cells in the bone marrow, digestive tract and hair follicles; this results in the most common side effects of chemotherapy : myelosuppression (decreased production of blood cells, hence also immunosuppression), mucositis (inflammation of the lining of the digestive tract), and alopecia (hair loss).

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SURGERYSurgery can be used to diagnose, treat, or even help prevent cancer in some cases. Most people with cancer will have some type of surgery. It often offers the greatest chance for cure, especially if the cancer has not spread to other parts of the body.

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HistoryThe discovery of platinum’s anticancer properties was

made by chance during an experiment in 1965, conducted at Michigan State University by Barnett Rosenberg. Rosenberg used a platinum electrode to apply an electric field to a colony of E. coli, which was observed to inhibit their growthHe was able to show that the compound cisplatin [Pt(NH3)2Cl2 ] was responsible for the effect and this was found to be effective against treating some cancers. The American Food and Drugs Administration (FDA) approved cisplatin for cancer therapy in 1978.It has since become the most widely used anticancer drug, with an estimated 70% of patients receiving thecompound as part of their treatment.

Cisplatin

BARNETT ROSENBERG

1926-2009

Pt

NH4Cl

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Geometric Isomers Differ in Behavior Geometric isomerism

occurs in both organic and inorganic compounds.

Diaminedichloroplatnium (II) (DDP) also called cisplatin is an inorganic complex that has been used to treat many different types of cancers.

Diaminedichloroplatnium (II) exists in both cis and trans isomers.

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Cisplatin is an effective anticancer drug, while Transplatin is not effective at all.

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Action of cisplatinCisplatin is a relatively unreactive molecule. In aqueous solution, however, the chloro ligands of cisplatin may be replaced in a stepwise manner as shown below:

-H+

-H+

+H2O

-Cl

+H2O

-Cl

To be effective, cisplatin must be activated by hydrolysis and loss of the chlorine atoms to produce a positive ion, which is highly electrophilic and capable of interacting with DNA.

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Cisplatin as an Anti-cancer Drug

• Cisplatin can diffuse through a cancer cell membrane.

• In the cell it exchanges a chloride ion for a water molecule forming a complex ion.

• This complex ion binds to the cancer cell DNA preventing it from replicating correctly.

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Fate of Cisplatin in the cell.

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Possible Mechanisms of cis-platinStructure of DNA

Deoxyribonucleic acid (DNA) is a molecule that encodes the genetic instructions used in the development and functioning of all known living organisms. DNA is a double-helix and has two strands running in opposite directions. Each strand has a backbone made up of (deoxy-ribose) sugar molecules linked together by phosphate groups. Each sugar molecule is linked to one of 4 possible bases (Adenine, Guanine, Cytosine and Thymine). A and G are double-ringed larger molecules (called purines); C and T are single-ringed smaller molecules called pyrimidines). In the double-stranded DNA, the two strands run in opposite directions and the bases pair up such that A always pairs with T and G always pairs with C.

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DNA binding Cisplatin binds to DNA and causes a critical structural change in the DNA – a bend of 45 degrees

Cisplatin binds to two adjacent G’s at N7 on the DNA.

this leads to the formation of interstrand or intrastrand cross-links of the DNA

block replication and/or prevent transcription ultimately causing cell death.

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Different modes of binding: Cisplatin-DNA Adduct

DNA 1,2-Intrastrand

Crosslink

1,2-Interstrand

Crosslink

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Mechanism of Cell Death

IT APPEARS THAT HMG PROTEIN DOES NOT OCCUR IN HEALTHY CELLS IN LARGE AMOUNTS AND THEREFORE CANNOT PROTECT AGAINST EXCISION REPAIR

Several mechanisms have been proposed to explain how HMG domain proteins might modulate the sensitivity of cells to cis- platin.Two of them seem to be the most feasible ones. “The HMG proteins could protect cisplatin-DNA adducts from recognition by DNA repair enzymes.”The second one establishes that“HMG proteins could modulate cell cycle events after DNA damage and trigger cell death.”

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High-Mobility Group or HMG is a group of proteins that are involved in the regulation of DNA-dependent processes such as transcription, replication, recombination, and DNA repair.

It has been found that the 1,2-intrastrand adducts are less effectively removed from DNA by repair enzymes than 1,3-intrastrand adducts. Further support for 1,2-intrastrand cross-links as the main adducts responsible for the antitumor activity of cisplatin came from the discovery that some HMG (high mobility group) domain proteins specifically recognize this type of DNA adduct . So, it has been proposed that specific HMG proteins may be involved in the cellular processing of the 1,2-intrastrand cross links formed by cis-DDP.

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Cisplatin and new drugs

From a clinical point–of-view the current challenges in drug development include:

addressing the poor solubility of cisplatin and analogues in water

cellular resistance of cancer cells to cisplatin toxic side effects of cisplatin

(e.g. nausea, neurotoxicity, kidney damage) use of platinum-based therapeutics to treat

cisplatin resistant cell lines

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(Satraplatin)

STRUCTURE OF 2nd GENERATION GRUGS

1979 1994

Approved in Japan

Approved in China

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CONCLUSION Cisplatin has become one of the most widely used anti cancer drugs and is highly effective in treating several cancers such as ovarian and testicular cancers.

Cisplatin binds to the DNA of cancer cells and brings about a critical structural change in the DNA which ultimately leads to cell death.

Though cisplatin shows remarkable antitumor activity, its large scale application is hampered due to its severe toxic side effects such as nausea, vomiting, bone marrow toxicity, neurotoxicity and renal toxicity.

The clinical application of cisplatin has increased enormously mainly as a result of improved administration procedures and its use in combination therapy, i.e. the simultaneous application of a variety of synergistic anti-tumor drugs.

The limitations of cisplatin have stimulated research in the field of platinum antitumor chemistry in trying to synthesize compounds with lesser or no toxic effects.

Some of the 2nd generation platinum based anticancer drugs are Carboplatin, Nedaplatin, Oxaliplatin, Lobaplatin and Satraplatin.

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