ANTICANCER DRUGS 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: 1. Relieve tumor related symptoms. 2.Improve overall quality of life. 3.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 Chemo.
2 types?
- Direct instillation into sanctuary sites (intrathecal or peritoneal)
- Regional perfusion of the tumor (e.g Intra-arterial)
Growth Fraction
what is it?
what type of tumor cells are more responsive to chemo?
• Growth fraction is 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.
What is the standard approach in the management of many tumor cells?
COMBINATION CHEMO -
1. Provides maximal cell kill within the range of
toxicity tolerated by the host for each drug.
2. Drug combinations are effective against a broader
range of cell lines.
3. Some combinations of anticancer drugs appear to
exert synergistic effect.
4. May prevent or slow the subsequent development of
cellular drug resistance.
Log Kill Hypothesis?
- the action of a cytotoxic drug follows first order kinetics!
- A given dose of chemo 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.
Common AE due to chemo. and tx?
most chemotherapeutic agents have toxic effects on normal cells, particularly those with rapid rate of turnover, such as bone marrow and mucous
membrane cells.
• Nausea and vomiting (treated with 5HT3 blockers and NK1 inhibitors). • Stomatitis • Alopecia • Myelosuppression (Filgrastim is used to treat neutropenia).
Strong myelosuppressors
"My strong Vin CADD" Cytarabine Alkylating agents Doxorubicin Daunorubicin Vinblastine
Moderate myelosuppression
Carboplatin
Methotrexate
5-FU
Mild Myeosuppression
“BAV”
Bleomycin
Vincristine
Asparaginase
Specific AE:
Doxorubicin
Cyclophosphamide and ifosphamide
Bleomycin
• Doxorubicin causes cardiotoxicity.
• Cyclophosphamide and ifosphamide cause
hemorrhagic cystitis (Mesna)
• Bleomycin causes pulmonary fibrosis.
Treatment-induced neoplasms are especially a problem after therapy with
alkylating agents.
Toxicity: minimizing AE: Leucovorin Mesna Dexrazoxane Filgrastim Amifostine
• Leucovorin rescues bone marrow from methotrexate.
• Mesna reduces hemorrhagic cystitis caused by cyclophosphamide and ifosfamide.
• Dexrazoxane reduces anthracycline (doxorubicin and daunorubicin)-induced
cardiotoxicity.
• Filgrastim reverses neutropenia caused by many
anticancer agents.
• Amifostine is a cytoprotective agent that reduces renal toxicity caused by cisplatin.
Most important efflux pump for multdrug resistance?
P-Glycoprotein (permeability glycoprotein) AKA MDR1
what cells are more sensitive?
cell cycling within the cell cycle..Not cell in Go phase.
Cell cycle specific vs Cell cycle non specific
• 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 lowgrowth
fraction solid tumors as well as in highgrowth-fraction
tumors.
Cell Cycle specific agents?
"Bleo CAME around" Antimetabolites Microtubule inhibitors Epipodophyllotoxins Camptothecins (TOPOTECAN, IRINOTECAN) Bleomycin
Cell cycle Nonspecific agents
“APA”
Alkylating agents
Platinum coordination complexes
Antitumor antibiotics
Antimetabolites
- Block S phase
Folate analogs
Purine analogs
Pyrimidine analogs
Methotrexate (MTX) MOA
- converted intracellularly to methotrexate polyglutamates which bind and inihibit DIHYDROFOLATE REDUCTASE.
- This results in inhibition of the synthesis of THF which is involved in denovo synthesis of:
- deoxythymidylate nucleotides → Inhibition DNA
synthesis. - Purine nucleotides → Inhibition DNA and RNA
synthesis
Leucovorin
MOA
• Leucovorin is N5-formyl-THF.
• Antidote to drugs that decrease levels of folic
acid, such as methotrexate, to rescue the bone
marrow.
• Leucovorin provides the normal tissues with the
reduced folate, thus circumventing the inhibition
of DHFR
Methotrexate Clinical applications?
• Breast cancer, head and neck cancer, osteogenic sarcoma, bladder cancer, choriocarcinoma,
primary central nervous system lymphoma and
non-Hodgkin’s lymphoma.
Methotrexate AE?
- Common: Stomatitis, mucositis, myelosuppression, alopecia, nausea, vomiting.
- Renal Damage: Uncommon. Complication of high-dose methotrexate.
- Hepatic fibrosis and cirrhosis.
- Pneumonitis.
- Neurologic Toxicities. With IT administration.
Purine analogs
6-Mercaptopurine
6-Thioguanine
- similar to hypoxanthine
6-Mercaptopurine MOA
- Converted to thio-IMP by the salvage pathway enzyme, HGPRT.
- Thio-IMP inhibits the first step of the denovo purine ring biosynthesis.
- Thio-IMP also blocks formation of AMP and GMP from IMP.
- Also, dysfunctional RNA and DNA result from incorporation of guanylate analogs.
6-Mercaptopurine CA/AE
Clinical applications:
• Childhood acute leukemia (ALL).
Adverse effects:
• Nausea, vomiting and diarrhea.
• Hepatotoxicity.
• Bone marrow suppression.
6 Thioguanine MOA
6-Thioguanine is converted to the nucleotide thioguanosine monophosphate (TGMP) by
HGPRT.TGMP then:
1. Inhibits the synthesis of the Purine nucleotides (by inhibiting PRPP amidotransferase).
2. Inhibit the phosphorylation of GMP to GDP by Guanylate kinase enzyme.
3. Can be converted to TGTP and dTGTP which incorporate into RNA and DNA respectively.
6 Thioguanine CA/AE
Nonlymphocytic leukemias
Adverse effects:
• Nausea, vomiting and diarrhoea.
• Hepatotoxicity.
• Bone marrow suppression
6-Thioguanine CA/AE
- Clinical applications:
• Nonlymphocytic leukemias.
AE:
N/V/D
Hepatotoxicity
Bone marrow supppression
Pyrimidine analogs
5-fluorouracil Capecitabine Deoxcytidine analogs - Cytarabine - Gemcitabine
5-Fluorouracil (5-FU) MOA
• Converted to the deoxyribonucleotide 5-FdUMP.
• 5-FdUMP inhibits thymidylate synthase. DNA synthesis is inhibited.
• ‘Thymineless death’ results.
• 5-FU is also converted to 5-FUTP and incorporated
into RNA, interfering with RNA processing and function.
5-Fluorouracil (5-FU)
Catalyzed by?
def of enzymes causes what toxic AE?
Dihydropyrimidine dehydrogenase (DPD) - def. of enzyme causes toxicity
- myelosuppression, neurotoxicity and life threateing diarrhea
5-Fluorouracil (5-FU) CA?
5-FU + Leucovorin combo used for colorectal cancer
- activity against a wide variety of solid tumors, including cancers of the breast,
stomach, pancreas, esophagus, liver, head and
neck, and anus.
• Can be used topically for keratoses and
superficial basal-cell carcinoma.
5-Fluorouracil (5-FU) AE?
N/V/alopecia, bone marrow depression!
- HAND FOOT SYNDROME
- seen after extended infusions!
Capecitiabine PK?
- Its a produrg of?
- how is it activated?
- MOA?
• Orally 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 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 - CA
1st line tx. for?
1st line for metastatic colorectal cancer.
Metastatic breast cancer
Capecitabine AE?
Diarrhea
Hand-Foot syndrome
Myelosuppression, N/V adn mucositis. incidence less than that observed w/ intravenous 5-FU.
Deoxycytidine analogs
Cytarabine (ARA-C)
Gemcitabine (dFdC)
Cytarabine (ARA-C)- MOA
Converted to Cytarabine triphosphate which then:
1. Competitively inhibits DNA polymerase-α (blockade of
DNA synthesis).
2. Competitively inhibits DNA polymerase-β (blockade of DNA repair).
3. 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:
Is it active against active tumors?
• Its activity is limited exclusively to hematologic
malignancies, including acute myelogenous leukemia
and non-Hodgkin’s lymphoma.
• Not active against solid tumors.
CYTARABINE-AE
- Myelosuppression
- Mucositis
- Nausea
- Vomiting
- Neurotoxicity (when high-dose therapy is administered).
GEMCITABINE MOA
- Phosphorylated to nucleoside di- and triphosphate, which inhibit DNA synthesis.
- Inhibition of ribonucleotide reductase by Gemcitabine DIphosphate, which reduces the level of deoxyribonucleoside triphosphates required for the synthesis of DNA.
- Incorporation of Gemcitabine TRIphosphate into DNA which results in chain termination.
GEMCITABINE CA?
What spectrum of activity has it got?
•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).
GEMCITABINE AE?
- Flu-like syndrome
- Nausea and vomiting
- Myelosuppression (neutropenia)
- Renal microangiopathy syndromes, including hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura (rarely).
MICROTUBULE INHIBITORS:
Inhibit Metaphase of Mitosis
Vinca Alkalloids:
Vinblastine
Vincristine
Taxanes:
Paclitaxel
Docetaxel
VINCA ALKALOIDS- PHARMACOKINETICS
- Metabolized by the liver P450 system.
- Excreted in feces.
- Dose modification is required in the setting of liver dysfunction.
VINCA ALKALOIDS-MOA
- Vinca alkaloids bind to β-tubulin. This disrupts assembly of microtubules.
- This inhibitory effect results in mitotic arrest in metaphase.
- Adverse effects of the Vinca alkaloids such as neurotoxicity may be due to disruption of these functions.
VINBLASTINE CA/AE
Clinical applications:
•Hodgkin’s and non-Hodgkin’s lymphomas, breast cancer and germ cell cancer.
Adverse effects:
•Bone marrow suppression (the dose-limiting adverse effect).
•Alopecia.
•Peripheral neuropathy.
•Nausea and vomiting.
*Potent vesicant, and care must be taken in its administration.
VINCRISTINE CA?
Clinical applications:
1. Hematological malignancies:
•Acute lymphoblastic leukemia, Hodgkin’s and non-Hodgkin’s lymphoma.
- Pediatric tumors:
•Rhabdomyosarcoma, neuroblastoma, and Wilms’ tumor.
VINCRISTINE AE
Adverse effects:
•Neurotoxicity with peripheral neuropathy.
•Paralytic ileus.
•Optic atrophy.
•Mild myelosuppression.
•Alopecia.
•Syndrome of inappropriate ADH secretion (SIADH).
TAXANES PK?
Pharmacokinetics:
•Metabolized extensively by the liver P450
- mostly excreted in feces via the hepatobiliary route.
•Dose reduction is required in patients with liver dysfunction.
TAXANES-MOA
- Taxanes bind to the β-tubulin subunit of microtubules at a site distinct from Vinca alkaloid binding site.
- Unlike the Vinca alkaloids, Taxanes promote microtubule polymerization and inhibit depolymerization.
- Stabilization of the microtubules in a polymerized state arrests cells in mitosis and eventually leads to the activation of apoptosis.
PACLITAXEL CA?
What kind of tumors?
•Solid tumors including: ovarian advanced breast, lung cancer, head and neck, esophageal, prostate, and bladder cancers and AIDS-related Kaposi’s sarcoma.
PACLITAXEL-ADVERSE EFFECTS
Hypersensitivity is one of the adverse effects, how is it reduced?
- Hypersensitivity, myelosuppression, peripheral neuropathy, alopecia, etc
- Hypersensitivity is reduced by premedication with dexamethasone, diphenhydramine and an H2 blocker
What is the significance of Abraxane?
•Abraxane is an albumin-bound form of paclitaxel which does not cause hypersensitivity, does not require premedication, and causes less myelosuppresion than the traditional paclitaxel.
DOCETAXEL CA?
- Second- line therapy in advanced breast cancer and non-small cell lung cancer.
- Major activity in head and neck cancer, small cell lung cancer, gastric cancer, advanced platinum-refractory ovarian cancer, and bladder cancer
DOCETAXEL-ADVERSE EFFECTS:
- Myelosuppression (dose-limiting).
- Fluid retention:Pre-treatment with Dexamethasone is required to prevent fluid retention.
- Neurotoxicity:does not cause neuropathy as frequently as Paclitaxel.
- Mucositis.
- Alopecia.
- Hypersensitivity.
EPIPODOPHYLLOTOXINS MOA
what are the 2 drugs?
•Inhibit topoisomerase II, resulting in DNA damage through strand breakage.
•Block cells in the late S-G2 phase.
ETOPOSIDE
TENIPOSIDE
EPIPODOPHYLLOTOXINS CA/AE?
Etoposide for testicular and small cell cancer.
Teniposide refractory childhood acute lymphoblastic leukemia
Adverse effects:
•Nausea and vomiting.
•Alopecia.
•Myelosuppression.
