Cancer Chemotherapy II Flashcards
What are the main classes of chemotherapy drugs?
Alkylating agents, antimetabolites, natural products, miscellaneous agents, and hormones/anti-hormones
What is the MOA of alkylating agents?
- Introduce alklyl groups into DNA, RNA and/or proteins
- Causes DNA crosslinks, strand breaks, and misreading of code
Give examples of cell-cycle specific and nonspecific alkylating agents
- cycle nonspecific= mechlorethamine, carmustine (BCNU)
- cycle specific (phase nonspecfici)= cyclophosphamide
**alkylating agents are the LEAST selective of all antineoplastics (tend to kill tumor and normal cells ~equally)
What are some toxic effects of alkylating agents?
- Nausea/vomiting
- Myelosuppression -> BM toxicity
- present for mechlorethamine
- limited for cyclophosphamide
- delayed for carmustine
- Hematopoiesis (WBC production) suppression
- GI effects
- Alopecia/hair loss (cyclophosphamide)
Define nadir
The lowest point (useful in cancer to determine low WBC count and adjust therapy accordingly)
What are the classes of alkylating agents?
- Nitrogen mustards= mechlorethamine, cyclophosphamide
- Nitrosoureas= carmustine (BCNU)
What is the MOA for mechlorethamine?
- cell cycle nonspecific
- bifunctional alkylating agent
- produces DNA crosslinks
- highly reactive, diappears from blood in sec-min
**used in combo therapy for hodgkin’s and non-hodgkin’s lymphoma
What are characateristics of cyclophosphamide? What is it used for?
- Prodrug activated by liver P450s
- Poor penetration into CNS
- Blader toxicity (sterile hemorrhagic cystits) that can be partially prevented with mesna
**Very broad spectrum; most widely used alkylating agent (for lymphoma, leukemia, breast/endometrium, lung cancer, etc)
What are characteristics of carmustine?
- Also called BCNU
- Cycle nonspecific
- Crosses the BBB very well (unlike cyclophosphamide)
What are common properties of antimetabolites?
- Structural analogs of compounds required for intermediary metabolism
- Greatest effectiveness in tumors where cell proliferation is rapid
- S phase specific
What is the MOA of methotrexate?
Binds to dihydrofolate reductase (DHFR) and prevents formation of tetrahydrofolate (needed for purine/pyrmidine synthesis)
What is leucovorin?
A fully reduced folate that does not require DHFR… Dose given after high doses of methotrexate (normal cells take up leucovorin better than tumors; save them but still kill cancer)
What are the side effects of methotrexate?
- Intestinal epithelium damage
- BM suppression
- Renal tubular necrosis
- Displaces other drugs from serum albumin
What are the uses for methotrexate?
- Acute lymphocytic leukemia
- Choriocarcinoma (rare tumor in pregnant women)
What is the MOA for fluorouracil?
- 5-FU; a pyrimidine analog
- Activated in cells to…
- FUTP which inhibits RNA synthesis
- FdUMP which interferes with thymidylate synthase -> ultimately inhibiting DNA synthesis
What are the side effects of 5-FU?
- Nausea, anorexia, diarrhea
- Myelosuppression
What are the uses for 5-FU?
**Broad spectrum of uses
- Stomach, colon, pancreas, bladder
- Ovary, breast
- Head and neck
- Basal cell carcinoma
(note: not for leukemia)
What is cytarabine (Ara-C)
- pyrimidine (cytidine) analog that competes for phosphorylation of cytidine
- competes for incorporation into DNA and causes chain termination
What are the side effects of cytarabine? What is it used for?
- Myelosuppression (dose limiting)
- Neurotoxicity
**used for acute leukemias (e.g. acute myelocytic leukemia)
What is gemcitabine?
Similar to cytarabine (also a pyrimidine analog) but also inhibits ribonucleotide reductase
**used in pancreatic cancer
What is the MOA of mercaptopurine?
- Purine analog
- Converted in cells to ribonucleotide that inhibits RNA and DNA synthesis
What are the side effects and uses of mercaptopurine?
- BM depression
- Vomiting, nausea, anorexia
- Jaundice
- ~10% patients have 1 nonfunctional copy of TPMT (thiopurine methyltransferase) gene and require reduced doses… <1% cannot get drug b/c they have 2 bad copies
**used for acute leukemias
What is the MOA of hydroxyurea?
- Inhibits ribonucleotide reductase
- Blocks conversion of ribonucleotides to dNTPs, therby preventing DNA synthesis
- Arrests cells at G1-S interface (useful with radiation; prevents cellular repair)
What are the side effects and uses for hydroxyurea?
- Hematopoietic depression
- GI disturbances
**used mainly in granulocytic leukemia
What is the MOA of vinca alkaloids? Examples?
Bind to tubulin, inhibiting proper formation of microtubules and mitotic spindles
**e.g. Vincristine and Vinblastine (structurally related but different toxicities and antitumor spectrums)
What are the side effects and uses of vinblastine?
- Strongly myelosuppressive (dose limiting)
- Epithelial ulcerations
**used to treat lymphomas and breast cancer
What are the side effects and uses of vincristine?
- Significantly less BM toxicity than vinblastine
- Alopecia
- Neuromuscular abnormalities (e.g. peripheral neuropathy)
**used for lymphomas, acute lymphocytic leukemia, Wilm’s tumor, neuroblastomas, and many others
What is the general MOA for taxanes?
- Enhance assembly and stability of microtubules by binding to beta subunit of tubulin (different binding site than vinca alkaloids)
- Blocks late in G2 phase (increased radiation sensitivity in G2)
What are the side effects and uses for paclitaxel?
- Dose limiting leukopenia
- Peripheral neuropathy
- Myalgia/arthralgia
**useful for refractory ovarian cancer and breast cancer
What is the MOA of doxorubicin?
- Intercalates in DNA, distorting DNA helix
- Causes lipid peroxidation and free radical generation
- Binds to DNA + topoisomerase II -> prevents resealing of DNA strand breaks
**cell cycle specific/phase nonspecific
What are the side effects and uses for doxorubicin?
- Cardiomyopathy
- BM depression
- Alopecia
- GI problems
**The most widely prescribed natural product chemotherapy (lymphomas, breast, ovary, small cell lung, and many others)
What is the MOA of bleomycin?
- Mixture of iron containing glycopeptides that bind to DNA (not active wihtout chelated Fe)
- Causes oxidative-like damage to DNA which leads to strand breaks
**phase specific for G2
What are the side effects and uses of bleomycin?
- Minimal myelosuppression
-
Pulmonary toxicity (e.g. pneumonitis, fibrosis)
- Dose related
- Cumulative and potentially fatal
- Skin vesiculations, hyperpigmentation
(lung and skin have lowest levels of bleomycin hydrolase)
**used for germ cell tumors of testes/ovaries, head/neck, lung, and lymphomas
What is the MOA of etoposide (VP16)?
- Stabilizes DNA topoisomerase II complexes (making them irreversibly bound to the ends of broken DNA)
- Results in dsDNA breaks that cannot be repaired
- Blocks in late G2 phase
What are the side effects and uses of etoposide?
- Leukopenia (dose limiting)
- Nausea, vomiting, diarrhea
- Alopecia
**used for lymphomas, actue leukemia, small cell lung, testis, Kaposi’s sarcoma, and others
What are biological response modifiers?
Naturally occuring proteins or therapeutic molecules designed to mimic or impact natural proteins (e.g. G-CSF, IFN, interleukins, TNF, TKIs, etc)
**Intended to alter a patient’s own biological response to a tumor or treatment regimen
What is filgrastim (G-CSF)?
**Granulocyte colony stimulating factor
- Goal is to limit chemo induced neutropenia
- Promotes progenitors of neutrophils
- Expands the absolute population of neutrophils -> quicker recovery from BM suppression
- SE= bone pain
What is imatinib?
(Gleevec)
- CKIT tyrosine kinase inhibitor
- An example of targeted drug therapy of KIT mutation in GI stromal tumors
What is the MOA of trastuzumab?
Humanized monoclonal Ab that binds the HER2 receptor (blocking proliferation of cells)
What are the side effects and uses of trastuzumab?
- Cardiomyopathy
- Hypersensitivity
- Infusion reactions (fever, chills)
**Used for breast cancers that overexpress HER2 (tend to be less responsive to anti-extrogen strategies and to many drugs except for doxorubicin and paclitaxel)
What is the MOA of cisplatin?
- Platinum coordination complex
- Hydrolysis yields activated species which causes DNA crosslinks
- Cycle specific and phase non-specific
What are the side effects and uses of cisplatin?
- Nephrotoxicity, Ototoxicity
- Peripheral neuropathy
- Electrolyte disturbances
- Nausea/vomiting
- Myelosuppression
**Wide antitumor spectrum; used for testicular, ovarian, head/neck, bladder, small lung, colon and esophagus cancers + more
What is the MOA of procarbazine?
Activated in vivo by liver enzymes to a methylating agent which causes chromosomal damage (an atypical alkylating agent, no cross-resistance with other alkylating agents)
What are the side effects and uses of procarbazine?
- Myelosuppression
- Nausea/vomiting
**Used for hodgkin’s lymphoma and several others
What tumors are hormone/anti-hormone chemotherapies most effective against?
Tumors that are steroid hormone dependent;
- 33% of all breast cancers respond to hormonal therapy
- 66% of breast cancers with good estrogen receptor
**presence of both estrogen (ER) and progesterone (PR) receptors in breast tumors increases the probability of response
What are the two possible strategies for hormone therapy?
- “Opposite” steroidal compounds
- e.g. estrogens for prostate cancer
- Anti-hormonal compounds
- e.g. antiandrogens for prostate cancer
- Decrease in growth fraction of responding tumor (hormone dependent)
- More cells in Go phase
**responses to hormonal therapy can be dramatic and prolonged… some benefitial SEs such as appetite stimulation
What is the MOA of prednisone?
- Binds to steroid receptors
- May arrest cells at G1
- Depresses expression of many growth related genes
- Induces nucleases which may modulate cell lysis
What are the side effects and uses of prednisone?
- Immunosuppression (at doses and duration generally used, there’s limited myelosuppression)
- Weight gain, fluid retention
- Psychologic effects
*Used for lymphomas, leukemia, and breast cancer… good in combination therapy
**Anti-emetic/stimulates appetite and anti-inflammatory
What are the antiestrogenic (ER+) classes and examples?
- Estrogen receptor antagonists
- Tamoxifen (TAM) and Raloxifene
- Non-steroidal
- Ietrozole
- Advantages; oral/rapid onset, estrogen below detectable levels, no androgenic SEs
What is the MOA of tamoxifen?
- Activated by CYP2D6 (ultrafast metabolizers have more side effects)
- Nonsteroidal antiestrogen that competitvely blocks estrogen receptor activity in breast tissue
- Generally cytostatic (holds cells in Go/G1)
- Stopping cell growth without necessarily killing the cells
- Tumor regrows when tamoxifen removed
What are the side effects and uses of tamoxifen?
- Nausea
- Hot flashes (menopause-like symptoms)
- Fatigue
- Bone and other musculoskeletal pain
- May increase rates of uterine/endometrial cancer (Raloxifene reduces risk)
**Used in advanced post-menopausal breast cancer, pre-menopausal metastatic breast cancer (estrogen competes), and breast cancer prophylaxis for women at high risk
What is aromatase?
P450 that converts androgens to estrogens (the major way of generating estrogen in post-menopausal women)
What is the MOA of letrozole?
Blocks conversion of androgens to estrogens by inhibiting aromatase (CYP19)
What are the side effects and uses of letrozole?
(Same as tamoxifen):
- Hot flashes
- Nausea
- Fatigue
- Bone and other musculoskeletal pain
**1st line treatment of post-menopausal locally advanced or metastatic breast cancer
What are the two antiandrogenic approaches to prostate cancer?
- GnRH analogs
- Leuprolide
- Non-steroidal androgen receptor blockers
- Flutamide
What is the MOA of leuprolide?
- Analog of GnRH
- After 2-4 weeks, it desenitizes GnRH signaling, decreasing LH/FSH and testosterone to castration levels
What are the side effects and uses of leuprolide?
- Hot flashes
- Impotence
**Used for advanced hormonally responsive prostate cancer
What is the MOA of flutamide?
Nonsteroidal antiandrogen that blocks androgen receptors
What are the side effects and uses of flutamide?
- Gynecomastia
- Diarrhea
- Hepatotoxicity (uncommon)
**Used in treatment of metastatic prostate cancer (in combination with GnRH agonist or other 2nd line therapy)
Describe how resistance develops to anti-neoplastics. What are the main mechanisms of drug resistance?
- Tumors will contain a small fraction (1 in 1,000,000 cells) that are resistant to a drug and its relatives
- Selection and overgrowth of these is a major cause of chemotherapeutic failure
- Resistance from…
- increased efflux/decreased influx
- activation of DNA repair/detoxifying systems (P450s)
- blocked apoptosis
Describe MDR
Multi-drug resistance can cause simultaneous resistance to many drugs (even those in different classes)
**Mediated by ATP-dependent drug efflux pumps
What are the main principles of combination chemotherapy?
- different cell cycle specifications
- active as single agents
- non-overlapping toxicities (note: vincristine, prednisone, and bleomycin lack significant BM toxicity)
- different MOAs
What other methods can be used in addition to just different mechanisms of combo therapy?
- sequential blockade
- concurrent inhibition
- complementary inhibition
- rescue
- synchronization
- recruitment
What is sequential blockade?
Simultaneous action of two inhibitors acting on different steps of a linear metabolic pathway (e.g. hydroxyurea and cytarabine)
What is concurrent inhibition?
Inhibitors block two separate pathways that lead to the same end product (no clear cut examples)
What is complementary inhibtion?
One drug affects the function of an end prodcut, the other drug affects the synthesis of that end product (or its precursors)
**e.g. cytarabine inhibits DNA synthesis and doxorubicin causes DNA damage
What is “rescue”?
“Rescue” the patient’s normal cells from the treatment
**e.g. leucovorin to rescue cells after high dose methotrexate, or autologous BM or stem cell transplant
What is synchronization?
Synchronize cells so they are in one phase and then use a drug that’s specific for that phase
*e.g. low dose fluorouracil to block in S phase, high dose cytarabine to kill in S phase
**attempts to synchronize in vivo have not proven very successful
What is recruitment?
Bring cells out of Go and back into cell cycle (mobilizing slowly proliferating or non-proliferating cells)
*combine with cell cycle non-specific drugs (mechlorethamine or carmustine/BCNU)
**aka bring non-dividing cells into cycle and then hit them with cycle specific drugs
