Lecture 26 / 27: Anti - Cancer Agents Flashcards
What are the 3 classes of Alkylating agents?
- Nitrogen Mustards
- Nitrosources
- Platinum Complexes
What are the 2 drugs in the nitrogen mustard class?
- Mechlorethamine
- Cyclophosphamide
1 drug in nitrosoureas class
Carmustine
1 drug in platinum complexes class
Cisplatin
What are the 3 classes of Antimetabolites?
- Folic Acid Analogs
- Purine Analogs
- Pyrimidine Analogs
What is the folic acid analog?
Methotrexate
What is the purine analog?
Mercaptopurine
What are the 2 pyrimidine analogs?
- Fluorouracil
- Cytarabine
What are the 2 classes of Natural products?
- Anthracycline antibiotics
- Vinca Alkaloids, Epipodophylotoxins and Taxanes (Plant products)
What are the 2 anthracycline antibiotics?
- Daunorubicin Hydrochloride
- Doxorubicin Hydrochloride
What are the 4 drugs in the Vinca alkaloids, epipodophylotoxins and Taxanes?
- Vinblastine Sulfate
- Vincristine Sulfate
- Etoposide
- Paclitaxel
What are the 2 classes of hormonal agents?
Adrenocorticosteroids
Estrogens and Antiestrogens
What are the 2 drugs in the adrenocortocosteroid class?
- Prednisone
- Dexamethasone
1 drug in the Estrogen and antiestrogen class
Tamoxifen
What is the 1 tyrosine kinase inhibitor?
Imatinib Mesylate
1 drug in the monoclonal antibody class
Trastuzumab
What is the goal of cancer chemotherapy?
To achieve selective toxicity against malignant tumor cells and spare normal host tissue.
What is the oldest successful drug in cancer treatment?
Mechlorethamine
Developed from mustard gas in WWI and WWII
Alkylating Agents MOA
- Cytotoxic effects via transfer of the alkyl groups to cellular constituents
- Alkylation of N7 guanine in DNA producing alkylated purine
- Results in cross-linking of DNA strands
What can alkylation of DNA strand result in?
- Miscoding of DNA strands or excising of guanine (depurination) results in strand break
- Incomplete repair of alkylated segment - lead to strand break or depurination
- Excessive crosslinking of DNA and inability for strand separation during mitosis (kills cell)
What type of alkylator agents usually cause miscoding of DNA and / or incomplete repair?
Monofunctional alkylator agents
What type of alkylators result in Excessive crosslinking of DNA and inability for strand separation?
Polyfunctional alkylators
During what phase of the cell cycle are cells most susceptible to alkylation?
Not cell cycle specific
Most susceptible in late G1 and S phases of cell cycle
Alkylating agent: Toxicity / 4 kinds
- Direct vesicant (vesicle producing) damaging tissues at site of injection
- Systemic toxicity - dose related / rapidly dividing cells are most affected
- Acute toxicity - nausea, vomiting (reduced with phenothiazines or cannabinoids)
- **Delayed toxicity **- bone marrow depression, immunosuppression, alopecia
- late secondary neoplasia including leukemia
Mechlorethamine hydrochloride: MOA / t1/2 / indications for use / route
- Alkylating agent
- Non-specific but M and G1 most sensitive
- t1/2 - 10 min
Indications:
* Hodgkin’s disease
Route:
* Instilled into pleural space; intravenous; topical
Cyclophosphamide: Pharmacologic properties
structure / metabolic activation / half-life / route
- Cyclic phosphamide derivative of mechlorethamine
- Requires metabolic activation by cytochrome P-450 in liver
- Half-life: 4-7 hours
- Intravenous, oral
Cyclophosphamide: Indications for use in cancers (7)
Acute and chronic leukemia:
* Hodgkin’s, non-Hodgkin’s and Burkitt’s lymphoma
* Multiple myelomas
* Testicular cancer
* Breast Cancer
* Lung Cancer
* Ovarian
* Endometrial and cervical carcinoma
Cyclophosphamide: Indications as Immunosuppressive agent
- Wegener’s granulomatosis
- Rheumatoid Arthritis
- Organ transplantation
Carmustine: Pharmacologic properties
type of alkylator / phase / solubility / half life / route
- Bifunctional alkylator
- Phase - nonspecific
- Highly lipid soluble
- half life: 90 min
- Oral / intravenous
Carmustine: Indications for use
- Brain tumors
- Hodgkin’s and non - Hodgkin’s lymphomas
- Multiple myelomas
Cisplatin: Pharmacologic properties
type / phase / effects / half life / toxicity / route
Type: Platinum coordination compound
Phase: non specific but G1 may be most sensitive
Half-life: 20-30 min
Toxicity: Nephrotoxicity and ototoxicity
Route: Intravenous
Cisplatin: Effect on DNA
- bifunctional alkylating agent (2 sites for binding)
- Causes inter - intrastrand DNA crosslinking
- Disrupts DNA double helix / interferes w/ synthesis
Cisplatin: Indications for use (not bolded)
- Testicular, ovarian, bladder, gastric, esophageal, pancreatic, lung, head and neck cancers
What is the most prevalent form of cross-linking caused by Cisplatin?
- 1,2 - intrastrand crosslink
- Platinum is covalently bound to the N7 position of adjacent purine bases
Primary MOA of antimetabolites?
Impede intermediary metabolism of proliferating neoplastic cells
Cell cycle specific agents
3 ways antimetabolites may inhibit metabolism in cancer cells?
- Drug may be metabolized instead of normal substrate (making molecule non-functional)
- May compete w/ normal metabolite at allosteric site
- May effect nucleotide and nucleic acid synthesis (most important)
Methotrexate: Pharmacological properties
enzyme / effect / protection of normal cells
- Inhibitor of dihydrofolate reductase - blocks conversion of folic acid to tetrahydrofolate
- Inability to convert deoxyuridylate to thymidylate (blocks RNA, DNA and protein syn.)
- Leucovorin (folinic acid) bypasses metabolic block (protects normal cells)
Methotrexate: Pharmacological properties
CNS penetration / plasma proteins / phase
- Poor CNS penetration - requires intrathecal use or high dose IV
- 50% bound to plasma protein
- cell cycle specific - kills cells in S phase
Methotrexate Toxicity: Acute / Delayed effects
- Acute effects: Nausea, vomiting, diarrhea
- Delayed effects: GI and oral ulceration, bone marrow suppression, alopecia, hepatotoxicity, pulmonary infiltrates, fever
Methotrexate: Indications for use
- Acute lymphocytic leukemia
- Non-Hodgkin’s lymphomas, leukemia, breast, pancreatic and bladder carcinoma
- Psoriasis, rheumatoid arthritis
Mercaptopurine: Pharmacological properties
analog of? / enzyme / inhibits / effects / metabolized by / phase?
Purine analog
* **Sulfhydryl-substituted **analog of hypoxanthine
* Converted by HGPRT (hypoxanthine-guanine phosphoribosyl transferase) to nucleotide form (6-thioinosinic acid)
* Inhibits enzymes of purine interconversion
* Causes inhibition of purine nucleotide synthesis (DNA / RNA)
* Metabolized by xanthine oxidase to 6-thiouric acid
Mercaptopurine: Toxicity
acute / delayed
Acute: infrequent nausea, vomiting, diarrhea
Delayed: gradual bone-marrow depression
Fluorouracil: Pharmacological Properties
active form / binds / blocks / phase
- Converted to active form 5 - deoxyuridine
- Covalently binds to** thymidylate synthetase **
-
Blocks conversion of deoxyuridylate to thymidylate (rate-limiting step of DNA syn.)
* Cell cycle specific (S Phase)
Fluorouracil: Indications for use
not highlighted
Carcinoma of:
* Breast
* Colon
* Pancreatic
* Ovarian
* Head
* Gastric
* Esophageal
* Head / Neck
Fluorouracil: Toxicity
Delayed toxicity
These drugs dont cause acute toxicity.
nausea, oral and gatrointestinal ulceration, bone marrow depression
Cytarabine: Pharmacological Properties
converted into / competes with / phase
- Converted to cytarabine triphosphate
- Inhibits DNA polymerase by competing with biological substrate (deoxycitidine triphosphate)
- Cell cycle specific (S-phase)
Cytarabine: Toxicity
not highlighted
Delayed toxicity
- Nausea
- Vomiting
- Bone Marrow Depression
- Megaloblastosis
- Leukopenia
- Thrombocytopenia
Cytarabine: Indications for use
not highlighted
- Remission induction in acute non-lymphocytic leukemia
- Acute lymphocytic leukemia
- Chronic myelocytic leukemia
- Meningeal Leukemia
What is overall MOA of many anti-cancer antibiotics? What are they derived from?
Bind to DNA through intercalation between specific bases and block DNA / RNA syn.
Derived from soil fungus streptomyces
Cell cycle non-specific
Daunorubicin hydrochloride & Doxorubicin hydrochloride: Pharmacological effects
MOA / effects / phase / antitumor activity / difference in structure
- MOA: intercalate and bind to DNA between base pairs on adjacent strands
- Results in uncoiling of DNA helix
- Destroys DNA template
- Non cell-cycle specific (max effect seen during S-phase)
- Structure differes by single hydroxyl group
Daunorubicin hydrochloride & Doxorubicin hydrochloride: Toxicity
acute / delayed
Acute: nausea, vomiting, red urine, tissue necrosis, arrhythmias
Delayed: bone-marrow depression, alopecia, GI upset and cardiomyopathy (important)
Daunorubicin: Indications
Acute non lymphocytic leukemia of adults
Greater activity than doxorubicin in acute lymphocytic leukemia (children and adults)
Doxorubicin: Indications
Lymphoma, leukemia, Hodgkin’s disease, carcinoma of breast, gastric, pancreatic, ovarian, lung, bladder neuroblastoma
Generally used in combination with other drugs with which it synergizes.
Vinblastine sulfate and Vincristine sulfate: Pharmacological effects
structure / bind to / effect / phase
- Similar structure: methyl group in vinblastine replaced w/ formyl group in vincristine
- Bind tubulin - component of microtubules
- Disruption of mitotic spindles / prevents chromosomal segregation
- Cell cycle - specific for mitosis
Vincristine: Toxicity
Acute / delayed
Acute: local reactivity if extravasated
Delayed: neurological, constipation, alopecia, mild bone depression
Vinblastine: Toxicity
Acute / Delayed
Acute: mild nausea, vomiting, phlebitis
Delayed: neurological and bone marrow depression
Vincristine and Vinblastine: indications
not highlighted
Vincristine: Breast carcinoma, acute leukemia, Hodgkin’s and non - Hodgkins
Vinblastine: Hodgkin’s disease, Kaposi’s sarcoma, testicular, bladder, lung carcinoma
Etoposide: Pharmacological Properties
Derivative of / forms what / results / phase specific
- aka VP-16. Semisynthetic derivative of podophyllotoxin
- Forms complex with topoisomerase II and DNA
- Results in DNA breaks, no repair and cell death
- Cell-cycle-specific for G2 phase
Etoposide: Toxicity
acute / delayed
Acute: nausea, vomiting, diarrhea (15% IV / 55% oral)
Delayed: Leukopenia (less than 4,000 WBC/mm3) 10-14 days and recover by 3 weeks
Alopecia (66%)
Etoposide: Indications for use
not highlighted
- Testicular cancer (w/ bleimycin and cisplatin)
- Small cell carcinoma of lung (w/ cisplatin)
Paclitaxel: Pharmacological Properties
extracted from / MOA / effect / phase specific
- Extracted from the bark of the Western (Pacific) yew
- Antimicrotubule agent
- Does not inhibit, but promotes microtubule assembly
- Enhances tubulin polymerization (stabilized microtubules)
- Cell cycle specific for G2 and M phase
Paclitaxel: Toxicity
Acute / Delayed
Acute: Nausea, vomiting (52 %)
Delayed: Bone marrow suppression (neutropenia, leukopenia, thrombocytopenia, anemia)
Hypersensitivity; peripheral neuropathy (60%)
Alopecia - pretty much everybody
Paclitaxel: Indications
- Metastatic Ovarian Cancer
- Metastatic Breast Cancer
- Non-small cell lung carcinoma
Prednisone and Dexamethasone: Cancer indications
Palliative management of leukemia and lymphoma in adults
Acute leukemia of childhood
Breast Cancer
Prednisone and dexamethasone: Anti-inflammatory and Immunosuppressive effects
- Affect concentration and distribution of peripheral leukocytes
- Concentration of PMN increases
- Concentration of lymphocytes (T/B cells), monocytes, eosinophils, basophils decreases
- Reduction of anigens and mitogens
- Reduction of cytokines
Prednisone and Dexamethasone: Effects on enzymes
Inhibits phospholipase A2 enzyme:
- Results in lower prostaglandin and leukotriene synthesis
- Induces secretion of lipocortins that inhibit PLA2
Inhibits cyclooxygenase 2 enzyme:
- Results in lower prostaglandin formation
Where are steroids metabolized?
Liver and excreted in the kidney’s
Steroids: Toxicity
short / long
Shorter (less than one week): Insomnia, behavioral changes, acute peptic ulcers and pancreatitis
Longer: iatrogenic Cushing’s syndrome
Steroids: Other adverse effects
- GI: Peptic Ulcers
- Increased bacterial and mycotic infections
- Adrenal suppression
- Obesity, dyslipidemia and glucose intolerance
Tamoxifen: Pharmacologic properties
type / inhibits / phase / route / t1/2 / metabolism
- Nonsteroidal antiestrogen
- Competitive inhibitor for estrogen receptors (nuclear transcription factors)
- G1 phase
- Oral
- half life of 7-14 days
- Extensive metabolism in liver and excreted in feces
Tamoxifen: Toxicity
short / long / most serious
