Cancer

The exploitation of microorganisms and of their products in the pharmaceutical industry

Cancer Cancer accounted for 7.1 million deaths world-wide (12.5%).

Ranks as 3 of the top 10 leading causes of death world wide.

11 million are diagnosed with cancer each year and by 2020 the World health organisation expects this rise to 16 million.

Second cause of death in the West (after cardiovascular diseases).

Sources: WHO and Cancer Research UK1Causes of cancerMultifactorial origin. Several factors associated with development of malignancy :

Radiation (sunlight and radio frequency)

Chemical carcinogens (polyaromatic hydrocarbons)

Mutagens and viruses (Human papilloma virus)

Others: tobacco, alcohol, diet, asbestos,

Genetic mutations within a single affected cell leads to monoclonal development. Genes affected can be those controlling cell cycle, DNA repair and/or differentiation, This leads to uncontrolled proliferation and tumour formation.

2Causes of cancer30% of cancer is due to smoking.30% of cancer cases is diet related.15% of cases are viral related infections:Papilloma virus sexually transmitted cause cervical cancer.Hepatitis-B is the cause of 80% of liver cancer.Some are bacteria related:H.pylori. Leads to stomach cancer.Terminology Cancer typesLeukaemias are cancers of the blood or bone marrow.

Sarcomas are cancers of the connective or supportive tissue (bone, cartilage, fat, muscle, blood vessels) and soft tissue.

Carcinomas are cancers that arises from epithelial cells. These include breast, liver, lung, stomach etc.

Cancer metastasis is the spread of cancer from the primary location to a secondary location.5Terminology Side effectsNeutropenia (or neutropaenia is a hematological disorder characterized by an abnormally low number of neutrophil granulocytes (a type of white blood cell).

Myelosuppression is a decrease in the production of blood cells. (Red blood cells and platelets).

Ototoxicity is damage of the ear, specifically the cochlea or auditory nerve.

Nephrotoxicity is kidney damage. Results in decreased kidney functions.

6Terminology Side effectsHepatotoxicity is liver damage. Results in decreased liver function.

Neuropathy is usually short for peripheral neuropathy, and means a damage to peripheral nerve(s).

Hypomagnesaemia is an abnormally low level of magnesium in blood serum.

7Treatment Course of treatment will depend on the type of cancer, progress of the disease, available treatment options and patients choice:

Surgery

Radiation

Chemotherapy (including combination therapy)

Gene therapy

Natural products/herbal8Problems with chemotherapy Treatments are non-specific, attack healthy cells as well as normal cells since cancer cells are derived from normal cells. Cancers can develop resistance: for example with platinum-drugs, cancer cells became resistant by many ways:

Decreased drug uptake/increased effluxEnhanced tolerance of DNA adductsEnhanced repair of DNA adductsIncreased drug deactivation by intracellular glutathione9Cancer treatmentBy surgery.By radiation.By anticancer drugs (cytotoxic agents):

Cytotoxic drugs of plant origin

Cytotoxic drugs of microbial origin

Antimetabolites

Alkylating agents

Platinum-based compounds

Ideal cytotoxic drugs should:Selectively target cancer cells without causing damage to normal cells. Reduce size of tumors + minimize risks of metastases.

unfortunately, most of the available agents are not selective, they also affect rapidly-proliferating normal tissues (bone marrow, gastro intestinal epithelium, hair cells, ), causing serious side-effects (bone marrow suppression, nausea, vomiting, ).

Cytotoxic drugs of plant originVinca alkaloidsVincristineVinblastineVindesineVinorelbine

Podophyllum lignansPodophyllotoxinEtoposide

Yew tree taxanesPaclitaxelDocetaxel

VincristinePodophyllotoxinEtoposide

PaclitaxelVinca alkaloids mainly used for Leukemiaand lymphomaPaclitaxel levels in plant is only 0.004%Paclitaxel*, Docetaxel(currently semi-synthesised)

10-deacetylbaccatin III(biosynthetic precursor)

10HHPaclitaxel mainly used for breast cancer and ovarian cancer

Doxorubicin R= -OHDaunorubicin R= -H

Anthracyclines mode of actionDNA intercalation

GuanosineDoxorubicinMethylene bridgeGuanosineHydrogen bondingDNA intercalation will prevent action of topoisomerase II (essential enzyme needed to untwist DNA)Antimetabolites

Folic acid(diet)GUTDihydrofolatereductaseDihydrofolateTetrahydrofolateMethylenetetrahydrofolateDihydrofolatereductaseThymidylate synthetasedUMP(uridine)dTMP(Thymidine)DNA synthesisFolate inhibitorsMethotrexate is an antifolate agentMethotrexate

Folic acid

Methyl groupAmine functionBinds more strongly than folic acid to DHFR and to carrier protein which transports folates into cells. Cells are starved of thymine. DNA production is impaired. Related to methotrexate structure

Fluorouracil

5fluorodeoxyuridine monophosphate binds irreversibly to the active site of thymidylate synthetase (C-F bond) instead of deoxyuridine monophosphate.Fluorouracil Stops the production of thymidineUsed in solid tumors

dUMP5-FdUMPCytarabine

Deoxycytidine triphosphateMimicAlkylating agentsVery reactive agents that alkylate cell constituents (DNA, enzymes, ). Possess a highly electrophilic centre (+) to react with nucleophilic groups (Nu -) such as OH, SH, NH.

The binding will be irreversible.No selectivity ( kill normal + cancer cells).

Mustards as alkylating agentsDiscovered after the development of sulphur mustard, a chemical agent used during World War 1.

Drugs cause depletion of white blood cells as s/e

Mustards mode of action

Clinically used mustards

Orally available through phenylalanine transport system Clinically used mustards

Cyclophosphamide is a prodrug

CyclophosphamidePhosphoramide group

Ifosfamide

4-hydroxy-cyclophosphamide.OXIDATION IN LIVERaldophosphamide tautomer.TUMOURabphosphoramideacroleinnormustine.Other alkylating agentsDo not necessarily contain nitrogen mustard, but it should have the electrophilic species which will react nucleic acids:Di-epoxide forming compounds:

Treosulfan (prodrug)p.o or IVFor ovarian cancer

DiepoxybutaneThe active electrophileOther alkylating agents

Tretamine ThiotepaBladder cancerEthyleneimine group

Busulfan bis-sulphonic acid esters safe enough to be given by mouth.site-specific delivery of cytotoxic Mustine alkylating agentsProstate tumour cells have abundant oestrogen receptor sites, and complexation of an Estradiol carrier with normustine enables accumulation of the complex within the tumour. The phosphate group provides water solubility, and the Carbamate linkage between the Mustine and the Estradiol deactivates the nitrogen lone pair through resonance stabilization, rendering the alkylating agent inactive when in the complex. Enzymatic hydrolysis in the tumour cell releases the active drug at the site of action.

Phosphate group improves water solubilitythe change of the amino group into the carbamateHas reduced the nucleophilicity of it.difficultTo form the aziridinium ring (less active).prodrugPlatinum-based drugs

Cisplatin

CarboplatinOxaliplatin

32They are prodrugs in general

Because this will increase the extracellular Cl- concentrationcompared to the intracellular

33Mechanism of action of cisplatinInduces cellular apoptosis by forming coordinate bonds to N7 atom of guanosine and adenosine bases. Results in unwinding of the DNA helix and a bend towards the major groove of up to 30o.

This prevents DNA transcription and Replication.

34

Interaction of the aquatic species with DNA: Formation of intrastrand bi-adducts blocking replication and/or prevent DNA transcriptionGuanineAdenineGuanineGuanineguanine-platinum-guanineguanine-platinum-adenineCarboplatin

Delivers the same active aquatic species as cisplatin, but with the chloride ligands replaced with carboxylate. preferred first line drug for ovarian cancer and small cell lung cancer) and is used particularly with patients who have poor tolerance of cisplatin.

36Oxaliplatin

First approved in 1999 for the use cisplatin and carboplatin resistant cancers One of three enantiomers, only the R,R-diaminocyclohexane ligand is active. Used primarily to treat colon/colorectal cancer.Good leaving groupResponsible for the lack in cross-resistance37Platinums in clinical trial

BBR3464 (0.9-1.1 mg/m2) Active in a range of cisplatin resistant cell lines

ZD0473 (120-150 mg/m2) Overcome glutathione-mediated resistance

JM216 (Satraplatin) Orally active38