cytotoxic cancer chemotherapy: antimetabolites, alkylating agents, Topoisomerase inhibitors, inhibitors of mitotic spindle (B32-34) Flashcards
Cancer therapy
Treatment depends on the type of cancer, the stage, age, health status and personal characteristics.
There is no single treatment for cancer. Patients often receive a combination therapies.
Surgery Radiation Chemo therapy Immuno therapy Hormone therapy Gene therapy Palliative therapy
EVIDENCE BASED MEDICINE!!!
Randomised, controlled, blinded clinical trials!!
ANTICANCER DRUGS
Cytotoxics
- poor efficacy, resistance, toxic side effects
1. antimetabolites,
2. DNA targeting drugs,
3. topoizomerase inhibitors,
4. mitotic inhibitors
Cytostatics
- hormone derivatives,
- cytokines,
- signal transduction modulators, enzymes
Characteristics of cytotoxic therapy
- Causes direct cellular damage leading frequently to cell death
- Tumor shrinkage is frequently observed if cell death is dominating
- has frequently poorly defined targets
- Host and tumor cells are equally damaged, toxicity is frequently severe
- Intermittent Therapy can be applied due to irreversible binding of the drug to the target and/or permanent cellular damage caused
- Continuous, prolonged administration causes lethal bone marrow damage, therefore intermittent administration is preferred to allow sufficient time for host tissue regeneration
Characteristics of cytostatic therapy
- Does not cause direct cellular damage, inhibits only cell
- Only tumor growth is inhibited, tutor shrinkage is only sometimes observed
- the molecular targets are well characterised
- Host toxicity compared to antitumor effect is usually mild
- Drug target binding is easily reversible, continuous therapy must be used
- Continuous, prolonged therapy can be maintained due to the mild toxicity to the host. Cumulative toxicity might be more severe
Chemotherapy
- acts on all rapidly dividing normal and cancerous cells
- compounds identified because they kill cells
- Cytotoxic- they kill tumor cells
used to:
- treat cancer: cure, lessen chance of return, stop or slow growth
- palliative care: shrink if it is causing pain or problem
- Neoadjuvant chemotherapy: make a tumor smaller before surgery or radiation
- adjuvant therapy: destroy cancer cells that may remain after surgery or radiation therapy
- Help other treatments, so they can work better
targeted therapy
- acts on specific molecular targets that are associated with cancer
- Compounds deliberately chosen or designed to interact with their target
- Cytostatic- they block tumor cell proliferation
Cytotoxic agenst
Antimetabolites: 1. 5-fluorouracil 2. Capecitabine 3. Cytarabine 4. 6-mercaptopurine (6-thioguanine) 5. Methotrexate 6. Pemetrexed (Hydroxyurea)
Alkylating agents: 1. Cyclophosphamide 2. Dacarbazine 3. Temozolomide 4. Cisplatin (Carboplatin) 5. Oxaliplatin
Intercalators:
- Dactinomycin
- Bleomycin
Topoisomerase inhibitors: 1. Irinotecan 2. Etoposide (Teniposide) 3. Doxorubicin (epirubicin)
Mitotic inhibitors: 1. Vincristine (Vinblastine) (Paclitaxel) 2. Docetaxel
https://www.youtube.com/watch?v=t7QDJOXeux4
Antimetabolites:
Pyrimidine antagonists:
- 5-fluorouracil
- Capecitabine
Dezoxycitidine analogs:
3. Cytarabine(Cytosine arabinoside)
Purinantagonist:
4. 6-mercaptopurine
(6-thioguanine)
Antifolate:
5. Methotrexate
6. Pemetrexed
(Hydroxyurea)
Alkylating agents:
- Cyclophosphamide
- Dacarbazine
- Temozolomide
- Cisplatin
(Carboplatin) - Oxaliplatin
An alkylating agent attaches alkyl groups to DNA bases – covalent bounds in DNA (mostly on guanine)
In the first mechanism an alkylating agent attaches alkyl groups to DNA bases. This alteration results in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases.
A second mechanism by which alkylating agents cause DNA damage is the formation of cross-bridges, bonds between atoms in the DNA. In this process, two bases are linked together by an alkylating agent that has two DNA binding sites. Cross-linking prevents DNA from being separated for synthesis or transcription.
The third mechanism of action of alkylating agents causes the mispairing of the nucleotides leading to mutations.
There are six groups of alkylating agents: nitrogen mustards; ethylenimes; alkylsulfonates; triazenes; piperazines; and nitrosureas.
Cyclosporamide is a classical example of the role of the host metabolism in the activation of an alkylating agent and is one or the most widely used agents of this class. It was hoped that the cancer cells might posses enzymes capable of accomplishing the cleavage, thus resulting in the selective production of an activated nitrogen mustard in the malignant cells. Compare the top and bottom structures in the graphic on the left.
Nitrogen Mustard and Cyclosporamide
Intercalators:
- Dactinomycin
2. Bleomycin
Topoisomerase inhibitors:
Topoisomerase I.:
1. Irinotecan
Topoisomerase 2.:
2. Etoposide
(Teniposide)
Anthtracyclins
3. Doxorubicin
(epirubicin)
Mitotic inhibitors:
Vinca alkaloids:
1.. Vincristine
(Vinblastine)
Inhibit polymerization of tubuline monomers
Taxanes:
(Paclitaxel)
2. Docetaxel
Microtubule-stabilizing, abnormal microtubules
Methotrexate
MOA:
- Antifolate
1. binds to the active catalytic site of dihydrofolate reductase
- inhibition of the synthesis of THF
- de novo synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine (–) down
- > S phase specific effect
Pk.:
- adm.: intravenous, intrathecal, or oral
- oral bioavailability is saturable
- elim.: mainly renal route (renal dysfunction!)
- aspirin, NSAIDs, penicillin, cephalosporins!
Ind.: acute lymphoid leukemia, non-Hodgkin lymphoma, breast, ovary, stomach, colon, bronchial cc., osteosarcoma smaller dose: RA, psoriasis (immune suppression)!
SE, toxicity: mucositis, GI, liver, kidney tox. hair loss bone marrow toxicity -> leucovorine (iv.)
Resistance:
- reduced folate carrier or folate receptor protein (decreased transport)
- decreased formation of cytotoxic MTX polyglutamates
- increased levels of the target enzyme DHFR through gene amplification
- reduced affinity for MTX (altered DHFR) (dihydro-folate reductase)
- multidrug resistance transporter P170 glycoprotein activation (decreased accumulation)
Pemetrexed
- antifolate
- approved for use in combination with cisplatin or monotherapy
- second-line therapy of NSCLC and mesothelioma
SE: myelosuppression, skin rash, mucositis, diarrhea, fatigue, and hand-foot syndrome (folic acid and vitamin B12 suppl.)
5-Fluorouracil (5-FU):
Fluoropyrimidines
pyrimidine antagonist
MOA:
- requires activation via a complex series of enzymatic reactions
- inhibition of DNA synthesis (“thymineless death.”)
- 5-fluorouridine-5′-triphosphate (FUTP) is incorporated into RNA
- fluorodeoxyuridine-5′-triphosphate (FdUTP), is incorporated into cellular DNA -> function and synthesis is decreases
- combined effects on both DNA- and RNA-mediated events
Pk.:
- iv. administration
- clinical activity is highly schedule-dependent
- extremely short half-life (10-15 min) -> infusion
- 80–85% atabolized by the enzyme dihydropyrimidine dehydrogenase (DPD)
- partial or complete deficiency of DPD: 5% of cancer patients
- > myelosuppression, diarrhea, nausea, vomiting, and neurotoxicity
Indication:
colorectal cancer!!
wide variety of solid tumors, including cancers of the breast, stomach, pancreas, esophagus, liver, head and neck, and anus
SE:
mucositis / stomatitis, diarrhoea
hand-foot syndrome
myelo suppression
Capecitabine:
Pyrimidine antagonist
undergoes extensive metabolism in the liver,
70–80% oral bioavailability metabolised to 5-FU- requires thimydine phosphorylase, in most cancer cells
Ind.:
metastatic breast cancer (might be combinated with docetaxel, paclitaxel, lapatinib, ixabepilone, and trastuzumab)
stage III and high-risk stage II colon cancer
metastatic colorectal cancer
-> capecitabine/oxaliplatin (XELOX) regimen
Toxicity: diarrhea, hand-foot syndrome myelosuppression, nausea and vomiting, and mucositis is less frequent than with 5-FU
Cytarabine
Deoxycitidine analogs (Pyrimidine analogs) Cytarabine (ara-C):
MOA:
- converted by deoxycytidine kinase to the 5′-mononucleotide (ara-CMP) -> -> ara-CTP
- inhibition of DNA polymerase-α and DNA polymerase-β
- > blockade of DNA synthesis and DNA repair
- incorporated into RNA and DNA
- S phase-specific antimetabolite
Pk.:
- rapid degradation -> continuous infusion over a 5–7 day period
- highly schedule-dependent activity
Ind.:
- no activity in solid tumors!!
- activity is limited exclusively to hematologic malignancies
- > acute myelogenous leukemia and non-Hodgkin’s lymphoma
SE:
- myelosuppression,
- mucositis,
- nausea and vomiting
- high dose: neurotoxicity
