Cancer is uncontrolled growth of abnormal cells in the body. (cancer cells don’t die) There are over 100 different types of cancer, and each is classified by the type of cell that is initially affected. Cancer cells are also called malignant cells.
Normal cells in the body follow an orderly path of growth, division, and death. Programmed cell death is called apoptosis, and when this process breaks down, cancer begins to form. Unlike normal cells, cancer cells do not experience apoptosis and instead continue to grow and divide. This leads to a mass of abnormal cells that grows out of control.
The basic differences between cancer cells and normal cells is that cancer cells characterized by : Uncontrolled cell proliferation. Decreased cellular differentiation Ability to invade surrounding tissues and Ability to establish new growth at ectopic site “metastasis”
Difference between benign and malignant (cancer) tumors that : Malignant tumors metastasize while Benign tumors don’t metastasize Metastasis: is a secondary growth originating from the primary tumor and growing elsewhere in the body.
Causes of cancer Environmental factors 90-95 % Radiations Smoking and alcohol Infections Chemicals Obesity Genetic factors 5-10%
Types of cancer treatment Surgery Used in conjugation with all types of treatment Radiation therapy Monoclonal antibodies Hormonal therapy
Immunotherapy It used as a follow-up therapy and it postpones the spread or recurrence of cancer Types of immunotherapy : Vaccines Interferons Interluekin -2
Chemotherapy Chemotherapy in cancer is mostly palliative (not curative) except for certain types of cancer e.g. Hodgking’s disease , lymphosarcoma , rhapdomyosarcoma Chemotherapeutic drugs are better at killing cycling cells “i.e. cells during DNA Synthesis” (s phase) and active division, that is more active against cycling than non-cycling cells.
Chemotherapeutic drugs have many side effects as : Bone marrow toxicity Nausea and vomiting Loss of hair Increased susceptibility to infection Teratogenic in pregnant women
Mechanism of action of chemotherapeutic agents divide into three mechanisms Stop the synthesis of pre DNA molecule building blocks e.g. folic acid and nucleotides Directly damage the DNA in the nucleus of the cell Effect on the synthesis or breakdown of the mitotic spindles
Stop the synthesis of pre DNA molecule building blocks e.g. folic acid and nucleotides These agents work to block some step in the formation of deoxyribonucleotides or nucleotides which are necessary in making of RNA & DNA . So When these steps are blocked , the nucleotides cannot be synthesized and these cells cannot replicate . Examples : methotrexate , fluorouracil and Mercaptopurine
Directly damage the DNA in the nucleus of the cell These agents chemically damage DNA and RNA. They disrupt replication of the DNA and either totally halts replication or cause the manufacture of nonsense DNA or RNA i.e. the new DNA or RNA does not code Examples : alkylating agents (e.g. Cisplatin) , daunorubicin and doxorubicin .
Effect on the synthesis or breakdown of the mitotic spindles Mitotic spindles help to split the newly copied DNA such that a copy goes to each of the two new cells during cell division. These drugs disrupt the formation of these spindles and therefore interrupt cell division. Examples :Vinblastine and Vincristine
Alkylating agents are compounds that are capable of introducing an alkyl group into nucleophilic sites on DNA , RNA or any enzyme through covalent bond . These agents are thought to react with the 7 position of guanine ( or any other nitrogen base) in each of the double strands of DNA, causing cross-linking that interferes with separation of the strands and prevents mitosis.
The effects of base alkylation include misreading of the DNA codon and single strand breakage of the DNA chain. However, the longtime effects are mutation and cell death. The favored site on DNA is at the N7 position of guanine, adenine, cytosine, and even the sugar phosphate groups .
Platinum based alkylating like agents Cisplatin Carboplatin Oxaliplatin Methylhydrazines Procarbazine
Nitrogen Mustards Methclorethamine Cyclophosphamide Melphalan Chlorambucil Ifosfamide The nitrogen mustards are cytotoxic chemotherapeutic agents similar to mustard gas which was used in WWI and WWII
Nitrogen mustards contain BIS(2-chloroethyl) group Modification of this group Change stability , reactivity and lipophilicity
Mechanism of Alkylation byNitrogen Mustards
Methclorethamine (2-chloro-N-(2-chloroethyl)-N-methyl-ethanamine) a strong vesicant and is taken By IV infusion and It used to treat prostate cancer . A major disadvantage of mechlorethamine is that it has mutagenic and carcinogenic effect on bone marrow stem cells.
Cyclophosphamide (N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide) This most widely used Alkylating agent It is inactive in vitro but When it administered it is Metabolized by liver into phosphoramide Mustard (active compound)
SAR of Cyclophosphamide Bis-2-chloroethylamino group is essential Chloro atom provides maximum activity Levo-isomer is inactive Triethylene derivative is inactive
phosphoramide Mustard is cytotoxic to cancer cells while acrolein is toxic to the bladder Cyclophosphamide may given orally but its absorption incomplete So it is better to be given I.V It used to treat many types of cancer such as lymphosarcomas , breast, ovarian, and lung cancer.
Nitroureas Carmustine(Gliadel®) Lomustine Streptozocin They are compounds that have nitroso (R-NO) group and a urea. They have little cross-resistance with other alkylating agents They cross blood-brain barrier So they used against brain tumors
Carmustine(N,N'-bis(2-chloroethyl)-N-nitroso-urea ) It cause alkylation of DNA At O-6 position of guanine It mainly used to treat brain cancer and lymphoma It cause pulmonary toxicity and nephrotoxicity
Alkyl sulphonates Busulfan (butane-1,4-diyl dimethanesulfonate) (Myleran®) It is used for treatment of chronic myelogenous leukemia (CML) in bone marrow Transplantation patients Main side effect is seizure
Platinum based alkylating like agents Cisplatin(Platinol®) Carboplatin Oxaliplatin These agents do not have an alkyl group, but They also damage DNA.They permanently coordinate to DNA to interfere with DNA repair (They trigger apoptosis) Platin is the only heavy metal compound in common use as a cancer chemotherapeutic agent
Cisplatin(diamminedichloroplatinum) It acts against cells that are actively synthesizing nucleic acids (S phase) and against cells in mitosis (M phase) the preferred site of binding is the N7 position of guanidine
Because it’s bifunctional (having two leaving groups) Cisplatin can form inter-strand DNA cross links which cause cytotoxicity It used in treatment of man-seminomatous testicular cancer and in ovarian cancer It is nephrotoxic agent
Methylhydrazines Procarbazine(N-isopropyl-4-[(2-methylhydrazino)methyl]benzamide) It must be converted into an azo derivative in vivo to become active against tumor cells. Alkylation of DNA or possible transmethylation may be the mode of action.
It is a component of the MOPP (Mechlorethamine, vincristine , procarbazine and predinsone) combination that is so effective in treatment of Hodgkins disease. It has monamineoxidase inhibition properties (MAOI) ,So it should not be taken with most antidepressants and certain migraine medications.
Refrences *Foy’s Principles of Medicinal Chemistry, chapter 42, sixth edition. **Foy’s Principles of Medicinal Chemistry, chapter 6, sixth edition Goodman & Gilman's The Pharmacological Basis of Therapeutics , eleventh edition Cancer chemotherapy--the first twenty-five yearsby R. B. Scott Handbook of Cancer Chemotherapy (6th edition)