ANTI-CANCERS Flashcards
INDICATIONS FOR CHEMOTHERAPY:
Chemotherapy is presently used in four main clinical settings:
- Primary (induction) chemotherapy .
- Neoadjuvant chemotherapy .
- Adjuvant chemotherapy .
- Site-directed chemotherapy.
PRIMARY CHEMOTHERAPY
- Chemotherapy administered as the primary treatment in patients who present with advanced cancer for which no alternative treatment exists.
- The goals of therapy are to:
- Relieve tumor related symptoms.
- Improve overall quality of life.
- Prolong time to tumor progression.
NEOADJUVANT CHEMOTHERAPY
- Chemotherapy is administered before surgery.
- The goal is to reduce the size of the primary tumor so that surgical resection can then be made easier.
ADJUVANT CHEMOTHERAPY
Administration of chemotherapy after local treatment modalities (e.g. surgery) has been performed.
Destroys microscopic cells that may be present after local treatment modalities has been done.
• Reduces the incidence of both local and systemic recurrence and to improve the overall survival of patients.
SITE-DIRECTED CHEMOTHERAPY
- Direct instillation into sanctuary sites (intrathecal or peritoneal).
- Regional perfusion of the tumor(e.g. Intra- arterial)
TUMOR SUSCEPTIBILITY TO CHEMOTHERAPY
GROWTH FRACTION?
- GROWTH FRACTION = the percentage of actively dividing cells at any given point in time.
- Malignant neoplasms with high growth fraction (E.g. leukemia and lymphoma) are more sensitive to chemotherapeutic drugs.
- Low growth fraction tumors (Solid tumor e.g. carcinomas of the colon, lung cancer) are less responsive to chemotherapeutic drugs.
TREATMENT PROTOCOLS FOR CHEMOTHERAPY
• Combination chemotherapy is the standard approach in the management of many tumors because it:
- Provides maximal cell kill within the range of toxicity tolerated by the host for each drug.
- Drug combinations are effective against a broader range of cell lines.
- Some combinations of anticancer drugs appear to exert
synergistic effect.
- May prevent or slow the subsequent development of cellular drug resistance.
LOG KILL HYPOTHESIS
- The log kill hypothesis proposes that the action of cytotoxic drugs follows first order kinetics.
- A given dose of chemotherapy kills a CONSTANT FRACTION of a tumor cell population (rather than a constant number of cells).
- Repeated doses of chemotherapy -with appropriate frequency- are required to eradicate the tumor cells.
CHEMOTHERAPY CHALLENGES:
- Toxicity of chemotherapy to normal cells.
- Most traditional chemotherapeutic agents currently in use appear to exert their effect on cell proliferation.
- Proliferation is a characteristic of many normal cells as well as cancer cells, most chemotherapeutic agents have toxic effects on normal cells, particularly those with rapid rate of turnover, such as bone marrow and mucous membrane cells.
- Resistance of tumor cells to chemotherapy.
CHEMOTHERAPY TOXICITY:
COMMON ADVERSE EFFECTS
1) NAUSEA/VOMITING
–> can be treated with 5HT3 blockers and NK1 inhibitors
2) STOMATITIS –> inflammation of the mucous membranes of the mouth
3) ALOPECIA –> HAIR LOSS
4) MYELOSUPPRESSION
FILGRASTIM is used to treat neutropenia
RESISTANCE TO CYTOTOXIC DRUGS
PRIMARY RESISTANCE
• No response to the drug on the first exposure.
ACQUIRED RESISTANCE
• Single drug resistance
- Due to increased expression of one or more genes.
- Multidrug resistance (MDR)
- Resistance emerges to several different drugs after _exposure to a single agent.***_
P-glycoprotein (permeability glycoprotein) is the most important efflux pump responsible for multidrug resistance. Hence the other name for this pump is multidrug resistance protein 1 (MDR1)
CLASSIFICATION OF ANTI-CANCER DRUGS
• Cell cycle-specific drugs:
Antineoplastic drugs that exert their action only on cells traversing the cell cycle.
Cell cycle-nonspecific drugs:
Can kill tumor cells whether they are cycling or resting in the G0 compartment. (Although cycling cells are more sensitive).
- In general cell cycle-specific drugs are most effective in hematologic malignancies and other tumors in which a large proportion of the cells are proliferating or are in the growth fraction.
- Cell cycle-nonspecific drugs are useful in low- growth fraction solid tumors as well as in high- growth-fraction tumors.
CELL CYCLE SPECIFIC AGENTS:
1) ANTIMETABOLITES
2) BLEOMYCIN
3) MICROTUBULE INHIBITORS
4) EPIPODOPHYLLOTOXINS
5) CAMPTOTHECINS
CELL CYCLE NON-SPECIFIC AGENTS
1) ALKYLATING AGNETS
2) PLATINUM COORDINATION COMPLEXES
3) ANTITUMOR ANTIBIOTICS
ANTIMETABOLITES (cell cycle specific agent)
1) FOLATE ANALOGS
2) PURINE ANALOGS
3) PYRIMIDINE ANALOGS
METHOTREXATE (MTX)
ANTI-CANCER ANTIMETABOLITE FOLATE ANTAGONIST
MTX undergoes Intracellular conversion to MTX polyglutamates which bind and inhibit dihydrofolate reductase(DHFR) enzyme.
This results in inhibition of the synthesis of tetrahydrofolate(THF) which is involved in denovo synthesis of:
- deoxythymidylate nuclotides → Inhibition DNA synthesis.
- Purine nucleotides → Inhibition DNA and RNA synthesis.
METHOTREXATE CLINICAL APPLICATIONS
AE:
• Breast cancer, head and neck cancer, osteogenic sarcoma, bladder cancer, choriocarcinoma, primary central nervous system lymphoma and non-Hodgkin’s lymphoma.
AE:
- Stomatitis
- Mucositis
- Nausea, vomiting and diarrhea.
• Myelosuppression.
- *• Pulmonary fibrosis.**
- *• Hepatotoxicity.**
LEUCOVORIN
-is folinic acid, is givin WITH methotrexate to avoid adverse effects
–> it provides cells with reduced folate to minimize side effects
6-MERCAPTOPURINE
MOA:
PURINE ANTAGONIST (ANTIMETABOLITE)
-has a very similar structure to HYPOXANTHINE
Mechanism of action:
Thiol analog of hypoxanthine.
Converted to the nucleotide 6-MP ribose phosphate (6-MPRP, also known as thio-inosinic acid or TIMP) by the salvage pathway enzyme, HGPRT.
TIMP inhibits phosphoribosyl pyrophosphate AMIDOTRANSFERASE enzyme which catalyzes the rate limiting step of the de novo purine ring biosynthesis.
Thio-IMP also blocks formation of AMP and GMP from IMP.
The monophosphate form is metabolized to the triphosphate form, which can then be incorporated into both RNA and DNA. This leads to dysfunctional DNA and RNA.
6-MERCAPTOPURINE
CLINICAL APPLICATIONS
ADVERSE EFFECTS?
Clinical applications:
6-MERCAPTOPURINE –> 6 y/o’s get it to help cap off their CHILDHOOD ALL
• _***Childhood acute leukemia (ALL).***_
Adverse effects:
- Nausea, vomiting and diarrhoea.
- Hepatotoxicity.
• Bone marrow suppression.
6-MERCAPTOPURINE
inactivated by what? Why is this a problem?
- 6-MP is inactivated by xanthine oxidase. This is an important issue because the Purine analog Allopurinol, a potent xanthine oxidase inhibitor, is used in the treatment of acute leukemias to prevent the development of hyperuricemia that often occurs with tumor cell lysis.
- Because Allopurinol inhibits xanthine oxidase, simultaneous therapy with allopurinol and 6-MP would result in increased levels of 6-MP, thereby leading to excessive toxicity. In this setting, the dose of 6-mercaptopurine must be reduced.
2. The 6-MP is also metabolized by the enzyme thiopurine methyltransferase (TPMT).
–> Patients who have partial or complete deficiency of this enzyme are at increased risk for developing severe toxicities this why the dose of 6-MP should be reduced.
6-THIOGUANINE
PURINE ANTAGONIST (ANTIMETABOLITE)
-converted to the nucleotide TGMP by HGPRT
–> TGMP then
- Inhibits the synthesis of the Purine nucleotides (by inhibiting PRPP amidotransferase).
- Inhibit the phosphorylation of GMP to GDP by Guanylate kinase enzyme
- Can be converted to TGTP and dTGTP which incorporate into RNA and DNA respectively.
6-THIOGUANINE
CLINICAL APPLICATIONS
6-THIOGUANINE –> 6-T –> ONLY has interactions with the TPMT (has no A in it so has NO interaction with ALLOPURINOL)
-Clinical applications:
• Nonlymphocytic leukemias.
- Adverse effects:
• Nausea, vomiting and diarrhoea. • Hepatotoxicity.
• Bone marrow suppression.
NOTE: HAS NO INTERACTION WITH ALLOPURINOL
but DOES get metabolized by the enzyme thiopurine methyltransferase (TPMT), in which a methyl group is attached to the thiopurine ring.
–> Patients who have partial or complete deficiency of this enzyme are at increased risk for developing severe toxicities this why the dose of 6-TG should be reduced.
PYRIMIDINE ANALOGUES
can only make pyramids out of 5 blocks, not out of 6 or any even number….. therefore 5-FLUOROURACIL (the 6’s are for purines)
will be A BIND to make a pyramid
1) 5-FLUOROURICIL
2) CAPECITABINE
3) GEMCITABINE
4) CYTARABINE
5- FLUOROURACIL
MOA
PYRIMIDINE ANALOG
- Is administered intravenously.
- Given topically for skin cancer.
- Is mainly catabolized by the enzyme ***_Dihydropyrimidine dehydrogenase (DPD).****_
- A partial or complete deficiency of the DPD enzyme results in severe toxicity.
MOA:
- inhibits THYMIDYLATE SYNTHASE –> decreases DNA synthesis
- also gets incorporated into RNA
5-FLUOROURACIL
clinical applications
AE
AE: 5-FLUOROURACIL –> hands and feet each and 5 fingers or toes therefore it gives you HAND-FOOT SYNDROME
COLON also has only 5 letters in it
• First line drug against COLORECTAL CANCER
It also has activity against a wide variety of solid tumors, including cancers of the breast, stomach, pancreas, esophagus, liver, head and neck, and anus.
Given topically for skin cancer.
AE:
Myelosuppression.
Gastrointestinal toxicity in the form of mucositis and diarrhea.
Neurotoxicity.
Skin toxicity manifested by the hand-foot syndrome.
CAPECITABINE
PYRIMIDINE ANTAGONIST
CAPE –> 4 limbs + CAPE –> therefore is a 5-FU prodrug. Is a superhero –> goes right to the tumor to get catalyzed for the last step
Orally available prodrug of 5-FU
Activated by a three-steps enzymatic conversion to 5-FU.
The first two steps occur in the liver .
The last step occurs in the tumor and it is catalyzed by the enzyme ***_Thymidine phosphorylase.***_
The expression of thymidine phosphorylase is higher in many solid tumors than in corresponding normal tissue, particularly in breast cancer and colorectal cancer.
CAPECITABINE
CLINICAL APPLICATIONS
ADVERSE EFFECTS
EXACT SAME AS 5-FU BUT LESS SIDE EFFECTS
• First-line treatment of metastatic colorectal cancer.
• Metastatic breast cancer. (superhero gets all the chicks)
AE:
• Diarrhea
Hand-foot syndrome.
Myelosuppression, nausea, vomiting, and mucositis are also observed with this agent, however their incidence is significantly less than that observed with intravenous 5-FU.
DEOXYCYTIDINE ANALOGS
1) CYTARABINE
2) GEMCITABINE
CYTARABINE
MOA
ABC –> Cytarabine BINDS/inhibits to the SITE (cyte) of DNA alpha and beta
• Converted to Cytarabine triphosphate which then:
- Competitively inhibits DNA polymerase-α (blockade of DNA synthesis).
- Competitively inhibits DNA polymerase-β (blockade of DNA repair).
- Incorporated into RNA and DNA. Incorporation into DNA leads to interference with chain elongation and defective ligation of fragments of newly synthesized DNA.
CYTARABINE
CLINICAL APPLICATIONS
AE
• Its activity is limited exclusively to hematologic malignancies, including
- acute myelogenous leukemia and
- non-Hodgkin’s lymphoma.
• Not active against solid tumors.
AE:
Myelosuppression
Mucositis
Nausea
Vomiting
Neurotoxicity (when high-dose therapy is administered).
GEMCITABINE
MOA
MOA: GEM that BINDS to and INHIBITS DNA in the TRIphosphate form
• Phosphorylated to nucleoside di- and triphosphate, which inhibit DNA synthesis.
This Inhibition is a result of:
- 1) Inhibition of ribonucleotide reductase by Gemcitabine diphosphate, which reduces the level of deoxyribonucleoside triphosphates required for the synthesis of DNA.
- 2) Incorporation of Gemcitabine triphosphate into DNA which results in chain termination.
GEMCITABINE
clinical applicaitons
AE
• Broad-spectrum activity against:
- Solid tumors: including Pancreatic cancer, non small cell lung carcinoma, bladder cancer, ovarian cancer, soft tissue and sarcomas.
- Hematologic malignancies :( non-Hodgkin’s lymphoma).
:( non-Hodgkin’s lymphoma).
AE:
Renal microangiopathy syndromes, including
1) hemolytic-uremic syndrome and
2) thrombotic thrombocytopenic purpura (rarely).
-can also have ELEVATED LIVER ENZYEMS (AST/ALT)
MICROTUBULE INHIBITORS
Microtubules are essential for formation of mitotic spindle.
–> required during MITOSIS
This class includes:
Vincaalkaloids:
A. Vinblastine.
B. Vincristine.
Taxanes:
A. Paclitaxel.
B. Docetaxel.
VINCA-ALKALOIDS
PK + MOA:
PK:
- Metabolized by the liver P450 system.
- Excreted in feces.
- Dose modification is required in the setting of liver dysfunction.
MOA:
- Vinca alkaloids bind to β-tubulin. This disrupts assembly of microtubules.
- This inhibitory effect results in mitotic arrest in metaphase.
- Microtubules are essential to many cellular functions such as movement, phagocytosis and axonal transport.
AE: of the Vinca alkaloids such as neurotoxicity may be due to disruption of these functions.
VINBLASTINE
VINCA-ALKALOID
Clinical applications:
• Hodgkin’s and non-Hodgkin’s lymphomas, breast cancer and germ cell cancer.
Adverse effects:
• Nausea and vomiting.
• Bone marrow suppression.
• Alopecia.
*Potent vesicant, and care must be taken in its administration.
VINCRISTINE
VINCA ALKALOID
Clinical applications:
1. Hematological malignancies:
• Acute lymphoblastic leukemia, Hodgkin’s and non- Hodgkin’s lymphoma.
_***2. Pediatric tumors:***_
• Rhabdomyosarcoma, neuroblastoma, and Wilms’ tumor.
ADVERSE EFFECTS:
Myelosuppression.
Alopecia.
Syndrome of inappropriate ADH secretion (SIADH).
_Neurotoxicity with peripheral neuropathy.****_
Paralytic ileus.
Optic atrophy.
BLEOMYCIN
ANTITUMOR ANTIBIOTIC: CELL CYCLE SPECIFIC
-is a cell cycle specific agent acting at G2
- Bleomycin is a small peptide that contains a DNA-binding region and an iron-binding domain at opposite ends of the molecule.
- It acts by binding to DNA, which results in single- and double-strand breaks following free radical formation.
ANTHRACYCLINES
AE
- Myelosuppression.
- Mucositis.
- Cardiotoxicity (treatment with the iron-chelating agent Dexrazoxane is approved to prevent or reduce anthracycline-induced cardiotoxicity).
***Erythema and desquamation of the skin observed at sites of prior radiation therapy “radiation recall reaction”.***
MECHLORETHAMINE
PK:
NITROGEN MUSTARD - ALKYLATING AGENT
Pharmacokinetics:
- Very unstable. Solutions must be made up just prior to administration.
- Largely replaced by cyclophosphamide, melphalan and other more stable alkylating agents.
- Powerful vesicant (given IV only). –> tends to cause BLISTERING
CHEMOMAN
