Cancer chemotherapy Flashcards
When are drugs more effective?
Drugs are more effective when a large proportion of tumor cell are proliferating.
High growth fraction.
Advantages and Disadvantage of using CCNS drugs
ADVANTAGES
They have a broad activity
Effective in slow-growing tumors
- Because they also target non-
specific dividing cells.
DISADVANTAGE
Increased Toxicity
- non-specific nature
- Can cause damage to normal cell
as well
Resistance
Cell Cycle Non-Specific drugs (CCNS)
Drugs that act on cancer cell in all phases. Including G0
Can kill both dividing and non-dividing cell.
S-phase Specific drugs
Antimetabolites
- Methrotrexate
- Fluorouracil
- Mercaptopurine
Examples of Cell cycle non-specific drugs.
- Alkalylation Agents
- Cyclophosphamide
- Cisplatin
- Lomustine
- Carmustine
- Antitumor antibiotics.
- Doxorubicin
- Bleomycin
- Mitomycin
General adverse effect of antineoplastic drugs ( Cancer drugs)
- Nausea/vomiting
- Alopecia= loss hair
- Myelosuppression= bone marrow loss
- Low WBC= Decrease immunity
- Ulceration of the mouth and IG
- Increase serum uric acid= increase risk of gout
- Secondary cancers= many cancer drugs mutate the DNA and can lead to another cancer.
Cell Cycle Specific Drugs (CCS)
They act on cancer cell during a specific phase of cell cycle.
S-phase, M-phase, G2 phase
Target in DIVIDING cells
Most effective agains the rapidly growing tumors.
Advantage and Disadvantage of cell cycle specific drug
ADVANTAGES
-Target action
-Fewer side effect on non-dividing cell
DISADVANTAGE
-Less effective on slow-growing tumor
-Toxicity on rapidly dividing normal cell. Like hair loss, GI symptoms, Myelosuppression.
M-phase Specific drugs
Microtubule inhibitors
Vinca Alkaloids
1. Vincristine
2. Vinblastine
Taxanes
1. Paclitaxel
2. Docetaxel
G2 phase Specific drugs
Toposiomerase II inhibitors
1. Etoposide
2. Teniposide
3. Irinotecan
4. Topotecan
Bleomycin
Tumor lysis syndrome
The anti cancer drug is causing this.
Occur when a large number of cancer cell die in response to therapy within a short period, releasing their content into the blood.
We can give Allopurinol to inhibit Xanthine Oxidase.
Rasburicase can inhibit Uric acid to Allantoin
Characteristics finding:
- Hyperuricemia
-Hyperkalecemia
-Hyperphosphatemia
- Hypocalcemia
Log-kill hypothesis
Chemotherapy drugs kill a constant fraction of tumor cell, rather than a constant number.
Initial treatment may reduce the tumor size but not eliminate it. We need multiple treatment cycles. Each cycle kills a fraction of the remaining cells. But the remain cell may become resistance over time
Role of combination therapy
Combination therapy
Optimizing therapeutic efficacy while minimizing toxicity.
Combining Drugs that act on different phases of the cell cycle.
Minimize resistance: Different mechanism of action. If some drugs are resistance to one drug they might be to the other one.
Non- overlapping Toxicities.
Primary induction chemotherapy
Primary treatment
Palliation- Relief of symptoms and suffering caused by cancer
extended time of tumor progression.
Neoadjuvant chemotherapy
Reduce the tumor size for better surgical outcome
Adjuvant chemotherapy
Procedure following after surgical procedure. To reduces risk of local and systemic recurrence.
Alkylating Agents
Are non-specific drugs
Alkalynation of nucleophilic group on DNA bases especially N-7 position of guanine.
Causes-
1. Cross linking of bases
2. Abnormal base pairing
3. DNA strand breakage.
Cyclophosphamide
Alkylating agent- non specific drug
- is a pro drug
- Hepatic cytochrome P450 enzyme converts it to its active metabolite ( phosphoramide mustard)
- Metabolite called Acroline that causes Hemorrhagic cystitis*. This can be reduced by Mesna.
- Also Cause SIADH
Mechlorethamine
Alkylating agent- non specific drug
Converts in the body to a reactive cytotoxic product.
Toxicity:
1. GI distress
2. Alopecia
3. Myelosupression
4. Sterility
5. Vesicant (blisters)
Procarbazine
Alkylating agent- non specific drug
Forms hydrogen peroxide, which generates DNA-damaging free radicals
Toxicity
1. GI distress
2. Myelosuppression
3. CNS dysfunction
4. Leukemogenic
5. Disulfiram like reaction ( is like the drug they give to alcoholics to stop drinking)
6. Inhibit monoamine oxidase (MAO)
Dacarbazine
Alkylating agent- non specific drug
Clinical use for Hodgkins lymphoma
(Epstein-Barr virus)
toxicity
1. GI distress
2. Alopecia
Carmustine and Lomustine
Alkylating agent- non specific drug
Nitrosoureas
Highly lipid soluble: Can cross BBB
DNA alkylation: cross linking
Useful for treatment of CNS cancer
Temozomide
Penetrates the CNS
Clinical use for
1. Anaplastic astrocytoma (brain tumor) refractory to nitrosoureas
2. Glioblastoma
Busulfan
Alkylating agent- non specific drug
Very important one
DNA alkylation: cross-linking
Clinical use:
1. Chronic myelogenous leukemia
Toxicity:
1. Skin pigmentation
2. Adrenal Insufficiency*
3. Pulmonary fibrosis*
Cisplatin
Carboplatin
Oxaliplatin
Alkylating agent- non specific drug
Platinum Analogs
Platinum atoms binds to DNA bases
Croslinks DNA
Toxicity of Cisplatin and Carboplatin
1. GI distress- Severe nauseas and vomiting*
2. Nephrotoxicity* ( can be reduced by using mannitol with severe hydration)
Toxicity of Oxaliplatin
Neurotoxicity*
But do NOT give nephrotoxicity
Antimetabolites
Cell specific drugs acting on S-phase
They have immunosuppressant action
Folic acid blocker- Methotrexate
Purine- Mercaptopurine and Thioguanine
Pyrimidines- Fluorouracil, Cytarabine and Gemcitabine
Methrotrexate (MTX)
Antimetabolite- S phase
Binds with high affinity to active catalytic site of Dihydrofolate Reductase and inhibits it *.
- Decrease the synthesis of
thymidylate (dTMP), purine,
pyrimidine and amino acids
- Interfere with protein metabolism
Resistance
1. Reduced drug accumulation
2. Changes in enzyme sensitivity/activity
3. Reduced formation of polyglutamate
Clinical uses:
1. Choriocarcinoma
2. acute leukemias
3. solid tumor
4. ectopic pregnancy
5. Rheumatoid arthritis
6. psoriasis
Toxicity-
1. Bone marrow suppression*
2. mucositis
3. Hepatotoxicity
- Leucovorin reduces the toxic effect of methotrexate on normal cell.
Mercaptopurine (6-MP) and Thioguanine (6-TG)
Purine Antimetabolites
Activation by HGPRTases*
inhibition of enzymes in purine metabolism.
Metabolism of 6-MP by xanthine oxidase is inhibit by Allopurinol and Febuxostat **
Clinical use: Acute leukemia, chronic myelocytic leukemia
Toxicity: bone suppression and hepatic dysfunction.
Cladribine
Purine antimetabolites
Converted to Cladribine triphosphate
Incorporated into the DNA and causes strands breakage and kills T cell.
Fluorouracil (5-FU)
Pyrimidine Antimetabolites
5-FU is converted into 5-FdUMP
5-FdUMP inhibits Thymidylate synthase* and inhibit DNA synthesis
Another metabolite called FUTP Interferes with RNA function.
Clinical uses:
1. Bladder, breast, colon and ovarian cancer
2. Topically for Keratoses and basal cell carcinoma.
Resistance:
Increased Thymidylate synthase activity ( basically is more than the drug)
Toxicity: Neurotoxicity (hand-foot syndrome)
Give them a dose of thymidine*
Cytarabine
Pyrimidine Antimetabolites
Convert to AraCTP- inhibits DNA polymerases*
Gemcitabine
Deoxycitytidine analog
Metabolite Gemcitabine diphosphate- inhibits ribonucleotide reductase - inhibit DNA synthase.
Vinca Alkaloids
Plant-base drug Works on M phase
- Vinblastine
- Vincristine
- Vinorelbine
Prevents assembly of tubulin dimers into microtubules. Block mitotic formation. *
Toxicity:
Neurotoxic * “glove and stocking” neuropathy
Clinical
Vinblastine and Vincristine- acute leukemias lymphomas
Vinorelbine- nonsmall cell lung cancer and breast cancer.
Taxanes
Pland-based drug - M phase cannot progress to Anaphase.
- Paclitaxel
- Docetaxel
Prevent the microtubule from disassembly into tubulin monomers. Interfere with mitotic spindle.
Hyperstabilize microtubules in M phase.
Toxicity:
Paclitaxel- Peripheral neuropathy “glove and stocking”* (same as Vinca)
Docetaxel- Neurotoxicity*
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