Anti-Neoplastics Pt. 2 Flashcards
What are the different classifications of Anti-Neoplastics (Based on mechanism of action)?
- Alkylating agents
- Antimetabolites
- Natural Products
- Miscellaneous agents
- Hormones and hormone antagonists
What mechanism do Alkylating agents use and what is the outcome of this interaction?
Alkylating agents introduce alkyl groups into DNA causing DNA crosslinks, strand breaks, and misreading of code
Describe cell-cycle specificity in terms of alkylating agents
Alkylating agents can be either
- Cell-cycle-nonspecific
- Affect all parts of cell cycle including G0
- mechlorethamine, carmustine
- Cycle-specific phase nonspecific
- Don’t include G0
- cyclophosphamide
Describe the 3 major side effects of alkylating agents
- Hematopoiesis suppression - Often used as an indicator of therapeutic effectiveness and normal cell recovery - bleeding and infection
- GI effects - damage to intestinal mucosa; nasuea/vomiting
- Alopecia (hair loss)
Nausea, Myelosuppression and Alopecia for
- Mechlorethamine:
- Cyclophosphamide:
- Carmustine:
- Mechlorethamine: Nausea, Myelosuppression and mild alopecia
- Cyclophosphamide: Nausea, limited Myelosuppression and alopecia
- Carmustine: nasuea, delayed myelosuppression and no alopecia
What is the meaning of a nadir in antineoplastics? Which drug reaches its nadir fastest?
The lowest or deepest point (lowest count of WBC after medication)
Cyclophosphamide reaches it’s nadir in 10 days
What are the classes of alkylating agents
- Nitrogen mustards (Mechlorethamine; Cyclophosphamide)
- Nitrosoureas (Carmustine)
- Alkyl Sulfonates
- Ethylenimines/Methyl-melamines
- Triazenes
Why is mechlorethamine considered a bifunctional alkylating agent?
- It produces DNA cross-links
- Highly reactive, disappears from blood in seconds to minutes (does not enter CNS)
Mechlorethamine is used in combination therapy for…
Hodgkin’s and non-Hodgkin’s lymphoma
Breast, lung, and ovarian cancer
What is the mechanism of action of cyclophosphamide?
Prodrug activated by liver cytochrome P450s
The phosphoramide mustard acts as an alkylating agent
Acrolein is a toxic decomposition product that causes sterile hemoorhagic cystitis
Cyclophophamide has a broad spectrum of activity - used against a wide variety of cancers
Most commonly used Alkylating Agent
How can you prevent the bladder toxicity associated with acreolein
Mesna
What are the properties of nutrosoureas? (Carmustine)
- Cycle nonspecific
- Cross the blood brain barrier very well (brain neoplasms)
- Treatment of brain tumors, multiple myeloma, melanoma
What are common properties among antimetabolites?
- Structural analogs of compounds required for intermediary metabolism
- Most effect in rapidly proliferating tumors
- S phase specific
What is the mechanism of action for methotrexate?
Binds to dihydrofolate reductase and prevents formation of tetrahydrofolate
Cancer cells polymerize MTX to MTX-polyglutamate more than normal cells (MTX-polyG is a more potent inhibitor of DHFR)
High doses of methotrexate are necessary to bind all DHFR - how do you rescue the host cells from damage?
Leucovorin = folinic acid, a fully reduced folate that does not require reduction by DHFR
Normal cells have increased capacity to bring in leucovorin relative to tumor cells
What are the side effects of methotrexate?
- Intestinal epithelium damage
- Bone marrow suppression
- Renal tubular necrosis (keep urine alkaline to limit this)
- Displaces other drugs from serum albumin
Indications for Methotrexate
Choriocarcinoma (NUMBER ONE TREATMENT)
Acute lymphocytic leukemia
Osteosarcoma
Mechanism of action of Fluorouracil (5-FU)
Pyrimidine analog that is activated in cells to FUTP which inhibits RNA synthesis and to FdUMP which interfferes with thymidylate synthase and ultimately DNA synthesis
Fluorouracil - Side Effects
Nausea, anorexia, diarrhea
Myelosuppression
Fluorouracil Uses
Broad spectrum of uses
- Stomach, colon, pancrease, breast, ovary cancer (mostly GI)
- Basal cell carcinoma
What is Cytarabine (Ara-C) and what is its mechanism?
Cytarabine is a pyrimidine analog that competes for phophorylation of cytidine - Competes for incorporationinto DNA and causes chain termination
Cytarabine
Side effects:
Administration and clearance:
Side effects: Marked myelosuppression (dose limiting) and neurotoxicity
Administration:
- Long continuous infusion (2x daily for 5 days)
- Increases probablilty of killing tumor cells not initially in S phase
- Very rapid metabolism - clears quickly
Use of Cytarabine?
Acute leukemias - Acute myelocytic leukemia (super effective)
Lymphomas
Head and neck cancer
Uses of…
Gemicitabine:
Cepecitabine:
Gemicitabine: Lung, Pancreatic, breast cancer
Cepecitabine: Breast, colon cancer
Mercaptopurine
Mechanism:
Side Effects:
Uses:
Mechanism: Purine analog - converted in cells to ribonucleotide that inhibits RNA and DNA synthesis
Side Effects: Bone marrow depression; vominiting, nausea, anorexia, Jaundice
Uses: Acute leukemias
When can administration of mercaptopurine be toxic
If patient has two copies of non functional TPMT (thiopurine methyltransferase), drug may reach toxic levels
10% of patients ahve 1 copy of nonfunctional TPMT and require reduced doses to prevent toxicity
Hydroxyurea - mechanism of action
- Inhibits ribonucleotide reductase
- Blocks conversion of ribonucleotides to dNTPs - prevents DNA synthesis
- Arrests cells at G1 - S interface - useful in conjunction with radiation
Hydroxyurea
Major uses:
Side Effects:
Major uses: Graulocytic leukemia
Side Effects: Hematopoietic depression, GI disturbances
Natural products (neoplastic drugs)
- Vinca alkaloids
- Taxanes
- Enzymes
- Epipodophyllotoxins
- Topoisomerase inhibitors
- Monoclonal antibodies
- Antibiotics
- Anti-angiogenic peptides/Biological response modifiers
- Vitamin A analogs
Vinca alkaloids
Mechanism:
Examples:
Mechanism: Binds to tubulin, inhibiting proper formation of microtubules and mitotic spindle
Example: Vincristine vs. vinblastine
- Different toxicities
- Different antitumor spectrum
Differences in side effects and treatments of Vinblastine vs. Vincristine
- Vinblastine
- Strongly myelosuppressive
- Epithelial ulcerations
- Treatment: Lymphomas/ Breast cancer
- Vincristine
- Significantly less bone marrow toxicity
- Alopecia
- Neuromuscular abnormalities
- Treatment: ALL, lymphomas, WIlm’s tumor, neuroblastoma
Taxanes (Paclitaxel)
Mechanism:
Enhances assembly and stability of microtubules by binding to β-subunit of tubulin (differnt binding site than vinca alkaloids)
Blocks late in G2 phase - this phase is more sensitive to radiation
What is the difference between Paclitaxel and Vinca alkaloids as far as actions on microtubules?
Polymerization is blocked by vincristine or vinblastine and stabilized by paclitaxel (prevent disassembly)
_______ + _______ has become the standard therapy for ovarian cancer
Paclitaxel + cisplatin
How does paclitaxel assist cisplatin or cyclophosphamide?
Side effects?
Paclitaxel can interfere with DNA repair, intensifying the effects of DNA damage by cisplatin or cyclophosphamide
- Side effects
- Dose limiting leukopenia
- Peripheral neuropathy
- Myalgia/arthralgia
Doxorubicin Characteristics
- Cycle-specific phase non-specific
- Among the most active of antitumore agents
- Wide spectrum of activity - Lymphomas, breast, ovary, small cell lung
What is one of the few drugs with some anti-angiogenic properties
Doxorubicin
Doxorubicin - mechanism (multi-faceted)
- Intercalates in DNA, distorting DNA helix
- Causes lipid peroxidation and free radical generation
- Binds to DNA + topoisomerase II - prevents resealing of DNA strand breaks
Doxorubicin side effects
Cardiomyopathy
Bone Marrow depression
Alopecia
GI problems
Bleomycin - Mechanism
- Mixture of iron-containing glycopeptides that bind to DNA
- Cause oxidative-like damage to DNA which leads to DNA strand breaks - only active with chelated Fe
- Both single and double stranded breaks
Bleomycin is phase-specific for _________
Active against:
Bleomycin is phase-specific for G2 (and M phases)
Active against: Germ cell tumors of testes and ovaries
- Head, neck, lung, lymphomas
Bleomycin side effects
- Minimal myelosuppression
- Pulmonary toxicity
- Skin vesiculation, hyperpigmentation
- Lung and skin have lowest levels of bleomycin hydrolase which inactivated bleomycin
Etopside (mandrake plant) mechanism:
Irreversibly stabilizes DNA topoisomerase II complexes
Results in dsDNA breaks that cannot be repaired
Blocks in late G2 phase (G2/M interface)
Etopside uses:
Side effects:
Etopside uses: Lymphomas, acute leukemia, small cell lung, testis, kaposi’s sarcoma
Side effects: Leukopenia, nausea, vomiting, diarrhea, alopecia
What are biological response modifiers (BRM)?
Naturally occuring proteins or therapeutic molecules designed to mimic or impact antural proteins
Many effects on cell cycle, oncogene expression
BRMs
Beneficial intent:
Limitations:
- Beneficial intent:
- Alter patient’s own biological response to a tumor or to treatment regimens
- Intent is to add potential benefit but less possibility for serious toxicity
- Limitations:
- Response can be variable
- Some have limited spectrum of action
What is the purpose of Filgrastim (G-CSF)?
It is a granulocyte colony stimulating factor meant to limit chemotherapy induced neutropenia
Promotes progenitors of neutrophils (expands population) and provides for quicker recovery from bone marrow suppression
Main side effect of filgastim?
Bone pain (33%)
Trastuzumab
Mechanism:
Use:
Side Effects:
Mechanism: Humanized monoclonal antibody that binds to HER2 receptor - blocks proliferation of cells
Use: Metastatic breast cancers that overexpress HER2
- Tend to be less responsive to anti-estrogen strategies and to many drugs except for anthracyclines and paclitaxel
Side Effects: Cardiomyopathy; hypersensitivity; infusion rxns
Cisplatin Mechanism:
Platinum coordination complex - hydrolysis yields activated species which causes DNA crosslinks
Also covalently binds and inhibits thioredoxin reductase - directly promotes apoptosis
Cisplatin
Specificity:
Use/Spectrum:
- Specificity: Cycle-specific phase-nonspecific
- Use/Spectrum: Wide antitumor spectrum
- Testicular cancer
- Ovarian cancer (with paclitaxel)
- Head, neck, bladder…
Cisplatin Side Effects
- Nephrotoxicity
- Ototoxicity
- Peripheral neuropathy
- Electrolyte disturbances
- Nausea, vomiting
- Myelosuppression
Cisplatin vs. carboplatin and oxaliplatin
_______ and _______ have narrower spectrum of action
______ is the best of the platinum agents at coorectal cancer
Carboplatin and oxaliplatin have narrower spectrum of action
Oxaliplatin is the best of the platinum agents at coorectal cancer
Procarbazine Mechanism:
Activated in vivo by liver to a methylating agent which causes chromosomal damage - atypical alkylating agent with not cross-resistance with other alkylating agents
Procarbazine Uses:
Side effects:
Procarbazine Uses: Hodgkin’s lymphoma (greatest effects in G1 and S phase)
Side effects: Myelosuppression, nausea, vomiting
Hormones and hormone antagonists in cancer therapy
- Useful against tumors that are steroid hormone dependent
- 33% of all breast cancers respond to hormonal therapy
- 66% of breast cancers with good estrogen receptor content respond to hormonal therapy
Possible strategies for hormone therapy (2)
Consequence?
- Opposite steroidal compounds - normal hormones promote tumor growth to administer “opposite” hormones
- Anti-hormonal compounds - block hormones
Consequence: decrease in growth fraction of responding tumor (more in G0 phase)
Prednisone mechanism of action
Binds to steroid receptors which act to modulate aspects of cell growth
- May arrest cells at G1
- Depress expression of many growth related genes
- Induce nucleases which may modulate cell lysis
Prednisone palliative effects
- Anti-emetic, stimulates appetite
- Anti-inflammatory
Potential complication of Prednisone:
Possible side effects:
Potential complication is immunosuppresion
May cause weight gain, fluid retention, and psychologic effects
Antiestrogenics
Estrogen receptor antagonists:
Aromatase inhibitors:
Estrogen receptor antagonists: Tamoxifen; Raloxifene
Aromatase inhibitors: Letrozole (non-steroidal)
Tamoxifen mechanism
Nonsteroidal antiestrogen that competitively blocks estrogen receptors in breast tissue - may prevent post menopausal osteoporosis
Downsides of Tamoxifen
- Generally cytostatic
- Tumor regrows when tamoxifen is removed
- Stops cell growth withot necessarily killing the cells
Tamoxifen uses:
Advanced post-menopausal breast cancer
Pre-menopausal metastatic breast cancer
Breast caner prophylaxis for women at high risk
Tamoxifen is activated by _______
CYP2D6
Tamoxifen side effects:
- Nausea
- Fatigue
- Hot flashes (menopause like symptoms)
- Bone and other musculoskeletal pain
The major way of generating estrogen in post-menopausal women is….
Aromatase
Letrozole - mechanism
Blocks conversion of androgens to estrogens by inhibiting aromatase - prevents stimulation of growth of ER+ cells
Aromatase inhibitors bind irreversibly to the heme of _____ (aromatase) which inhibits conversion of androgens to estrogens
CYP19
Uses of Letrozole
1st line treatment of post-menopausal locally advanced or metastatic breast cancer
Side effects of Letrozole AND tamoxifen
Hot flashes
Nausea
fatigue
bone and other musculoskeletal pain
Tamoxifen does not decrease ______ _______ whereas aromatase inhibitors have been associated with decreased ______ _______ (same word)
bone density
Antiandrogenic approaces to prostate cancer:
GnRH analogs:
Non-steroidal androgen receptor blockers:
GnRH analogs: Leuprolide
Non-steroidal androgen receptor blockers: flutamide
Leuprolide - mechanism of action
- Analog of GnRH
- Initially stimualtes LH and FSH release causing testosterone surge and disease flare
- After 2-4 weeks, it desensitizes GnRH signaling, decreasing LH/FSH and testosterone to castration levels
Leuprolide - approved use
Side effects:
Advanced hormonally responsive prostate cancer - Most common 1st line drug therapy
Side Effects: Hot flashes; impotence
Flutamide
Mechanism:
Treatment:
Side Effects:
Mechanism: nonsteroidal antiandrogen that blocks androgen receptors
Treatment: metastatic prostate cancer
Side Effects: gynecomastia, diarrhea, hepatotoxicity
What is a major cause of chemotherapeutic failure?
Selection and overgrowth - most tumors will contain a small fraction of cells that are likely resistant to one drug
_______ _________ is a key strategy in overcoming resistance
combination therapy
Multi-Drug resistance (MDR) - how is it mediated?
What drugs is MDR especially prominent for?
Mediated by ATP-dependent drug efflux pumps
Especially prominent for:
- Vincristine; vinblastine
- Doxorubicin, bleomycin
- Etopside
- Paclitaxel
Principles of combination chemotherapy
- Different cell cycle specificities
- Active as single agents
- Non-overlapping toxicities
- DIfferent mechanisms of action
Strategies to delivery of combination chemotherapy:
Sequential blockade
Concurrent inhibition
Complementary inhibition
Rescue
Synchronization
Recruitment
- Sequential blockade
- simultaneous action of two inhibitors acting on different steps of linear pathway
- Concurrent inhibition
- Inhibitors block two separate pathways leading to same product
- Complementary inhibition
- One drug affects function of an end product and other affects synthesis of that product
- Rescue
- Rescue the patients normal cells from treatment
- Synchronization
- Push cells into one phase and then use drug specific for that phase
- Recruitment
- Bring cells out of G0 and back into cell cycle
(DO NOT HAVE TO MEMORIZED) - Examples of
Sequential blockade
Concurrent inhibition
Complementary inhibition
Rescue
Synchronization
Recruitment
Sequential blockade: Hydroxyurea + cytarabine
Concurrent inhibition: no clear cut examples
Complementary inhibition: cytarabine inhibits DNA synth; Doxorubicin causes DNA damage
Rescue: Leucovorin to rescue cells after methotrexate exposure
Synchronization: Low dose fluorouracil to block in S phase; high dose cytarabine to kill in S phase
Recruitment: alkylating agents (mechlorethamine) or nitrosureas (carmustine) then hit with cycle-specific drugs
