Cancer Chemotherapy: Firoz Anwar
Cancer Chemotherapy: Firoz Anwar
Cancer Chemotherapy: Firoz Anwar
Firoz anwar.
100 trillion cell,100billionCell new cells daily, mitosis,mutation,apoptosis,mitosis(neopla sma.tumor)contact inability,supergrowt,invasiveness,mutation, metastasis,cancer
Cancer
One type of neoplasm (tumor), which is an abnormal mass of tissue, the growth of cell exceeds & is uncorordinated with that of normal tissue & persists in same excessive manner even after the cessation of the stimuli Two types: 1. Benign tumor: remain localised, cant spread to other sites 2. Malignant tumor: can invade, destroy adjacent structures and spread to distant sites
Pathogenesis
Cell Cycle
Bleomycin
Podophyllin Alkaloids Plant Alkaloids
Increased expression of MDR-1 gene for a cell surface glycoprotein, P-glycoprotein MDR-1 gene is involved with drug efflux Drugs that reverse multidrug resistance include verapamil, quinidine, and cyclosporine MDR increases resistance to natural drug products including the anthracyclines, vinca alkaloids, and epipodophyllotoxins
Schematic of P-glycoprotein
Alkylating Agents
Nitrogen Mustards Ethylenimines Alkyl Sulfonates Nitrosoureas
Cyclophosphamide
Thiotepa
Busulfan
Carmustine
Legend
Drug Class Sub-class Prototype Drug
Alkylating Agents
Mechanism of Action
Alkylate within DNA at the N7 position of guanine Resulting in miscoding through abnormal base-pairing with thymine or in depurination by excision of guanine residues, leading to strand breakage Cross-linking of DNA and ring cleavage may also occur
Alkylating Agents
Mechanism of Action
Nitrogen Mustards
Cyclophosphamide Ifosfamide Mechlorethamine Melphalan Chlorambucil
Cyclophosphamide Metabolism
Nitrosoureas
Carmustine Lomustine Semustine Streptozocin-naturally occuring sugar containing /cross-link through alkylation of DNA /All cross the blood brain barrier
Alkylating-Related Agents
Procarbazine Dacarbazine Altretamine Cisplatin Carboplatin
These compounds alkylate N7 of guanine. They cause nephro- and ototoxicity. To counteract the effects of nephrotoxicity, give mannitol as an osmotic diuretic, or induce chloride diuresis with 0.1% NaCl.
Bone marrow depression, with leukopenia (DECREASE IN WBC)and thrombocytopenia(low pletelet count)
Cyclophosphamide/Ifosfamide - hemorrhagic cystitis(inflam bladder)
Reduced
Used to treat a wide variety of hematologic and solid tumors Thiotepa ovarian cancer Busulfan chronic myeloid leukemia Nitrosoureas - brain tumors Streptozocin insulin-secreting islet cell carcinoma of the pancreas
Antimetabolites
Folic Acid Analogs
Methotrexate
Purine Analogs
Mercaptoguanine
Pyrimidine Analogs
Fluorouracil
Folate
An essential dietary factor, from which THF cofactors are formed which provide single carbon groups for the synthesis of precursors of DNA and RNA To function as a cofactor folate must be reduced by DHFR to THF
Methotrexate
Mechanism of Action
The enzyme DHFR is the 1 site of action MTX prevents the formation of THF, causing an intracellular deficiency of folate coenzymes and accumulation of the toxic inhibitory substrate, DHF polyglutamate The one carbon transfer reactions for purine and thymidylate synthesis cease, interrupting DNA and RNA synthesis
GAR
IMP
5,10-CH2THF dUMP
5-CH3THF
DNA
*from Bowen
Homocysteine
a,thymidylate synthase; b, dihydrofolate reductase; c, methylenetetrahydrofolate reductase; d, methionine synthase; e, serine hydroxymethyl transferase aminoimidazole carboxamide ribonucleotide
Resistance
Methotrexate
Mechanism of Resistance
1.
2. 3. 4.
Decreased drug transport Altered DHFR Decreased polyglutamate formation Increased levels of DHFR
Methotrexate
Therapeutic Uses
Methotrexate- psoriasis, rheumatoid arthritis, acute lymphoblastic leukemia, meningeal leukemia, choriocarcinoma(PLACENTA), osteosarcoma, mycosis fungoides, Burkitts(b lymphocy) and nonHodgkins lymphomas, cancers of the breast, head and neck, ovary, and bladder
Trimetrexate
Therapeutic Uses
Trimetrexate- Pneumocystis carinii pneumonia, metastatic colorectal carcinoma, head and neck carcinoma, pancreatic carcinoma, non-small cell carcinoma of the lung
Pemetrexed
Therapeutic Uses
Methotrexate
Toxicity
Nephrotoxic
give
Purine Antagonists
Mercaptopurine Thioguanine Fludarabine Phosphate Cladribine
Mercaptopurine/Thioguanine
Must metabolized by HGPRT Hypoxanthine-guanine phosphoribosyltransferase to the nucleotide form This form inhibits numerous enzymes of purine nucleotide interconversion
Fludarabine Phosphate
- phosphorylated intracellularly by deoxycytidine kinase to the triphosphate form The metabolite inhibits DNA polymerase- and ribonucleotide reductase Induces apoptosis Tx- non-Hodgkins lymphoma and chronic lymphocytic leukemia
Cladribine
-phosphorylated by deoxycytidine kinase and is incorporated into DNA Causes DNA strand breaks Tx- hairy cell leukemia, chronic lymphocytic leukemia, and non-Hodgkins lymphoma
Pyrimidine Antagonists
Fluorouracil - S-phase Cytarabine Gemcitabine Capecitabine
MTX
5-FU
Figure 2. This figure illustrates the effects of MTX and 5-FU on the biochemical pathway for reduced folates.
5-FU inhibits thymidylate synthase therefore causing depletion of Thymidylate 5-FU is incorporated into DNA 5-FU inhibits RNA processing
Activation of 5-FU
Cytarabine
It is activated to 5 monophosphate (AraCMP) by deoxycytidine kinase Through a series of reactions it forms the diphosphate (AraCDP) and triphosphate (AraCTP) nucleotides Accumulation of AraCTP potently inhibits DNA synthesis Inhibition of DNA synthesis is due to competitive (-) of polymerases and interference of chain elongation
Cytarabine
It is a potent inducer of tumor cell differentiation Fragmentation of DNA and evidence of apoptosis is noticed in treated cells AraC is cell-cycle specific agent, it kills cells in the S-phase
Cytarabine
Toxicities
Nausea acute myelosuppression stomatitis alopecia
Gemcitabine
Gemcitabine is S-phase specific it is a deoxycytidine antimetabolite it undergoes intracellular conversion to gemcitabine monophosphate via the enzyme deoxycytidine kinase it is subsequently phosphorylated to gemcitabine diphosphate and gemcitabine triphosphate
Gemcitabine
Gemcitabine triphosphate competes with deoxycytidine triphosphate (dCTP) for incorporation into DNA strands do to an addition of a base pair before DNA polymerase is stopped, Gemcitabine inhibits both DNA replication and repair Gemcitabine-induced cell death has characteristics of apoptosis