Anti-Neoplastics Drugs Flashcards
What are the three alkylating agents?
Mechlorethamine
Cyclophosphamide
Carmustine
Procarbazine
How do the alkylating agents work and what do they target?
Introduce alkyl-groups into DNA (+ other various targets)
causing DNA cross-linking and strand breaks.
What are the alkylating agents that is cell-cycle nonspecific?
Mechlorethamine
Carmustine
Target any tumor cells in any phase
What alkylating agent is cell-cycle specific, phase nonspecific?
Cyclophosphamide - targets any dividing cell, not G0
How do the myelosuppression of the alylating agents compare?
Cyclophosphamide = Limited suppression Carmustine = Delayed suppression Mechlorethamine = Most suppression
What alkylating agent can pass the blood-brain barrier?
Carmustine, due to high lipophilicity.
What alkylating agent is used in combination Hodgkin’s Lymphoma and has a very short half-life?
Mechlorethamine
What alkylating agent is a pro-drug and what is a unique side effect?
Cyclophosphamide. Must be activated by cytochrome.
Produces phosphoramide (active) and Acrolein (toxic).
Acrolein can cause bladder toxicity, sterile hemorrhagic cystitis.
What alkylating agent has the widest spectrum of treatment?
Cyclophosphamide, cycle-specific, phase nonspecific
What kind of cancers does Carmustine treat?
Brain tumors
Multiple myeloma
–Only one that can cross the blood-brain barrier quickly–
What class of anti-neoplastics specifically target cells that are in the S-phase?
Anti-metabolites, analogs of compounds required for metabolism.
What drug prevents the recycling of tetrahydrofolate for thymidine synthesis?
Methotrexate, inhibits DHFR, preventing reduction of folate
How is Methotrexate used and how are normal cells spared?
Methotrexate can be used in large doses, then given Leucovorin to “rescue” normal cells, due to their ability to import the Leucovorin inside more easily.
(fully reduced folate)
What should be watched when treating a patient with Methotrexate?
- bone marrow suppression
- renal tubular necrosis
- *Other drugs that can displace Methotrexate from Albumin (how it’s transported)**
What kind of cancers is Methotrexate typically used for?
Acute Lymphocytic Leukemia
Choriocarcinoma
What anti-metabolite is a uracil analog and what are it’s effects?
Fluorouracil (5FU)
- becomes activated in the cell, converted to:
5UTP = inhibits RNA synthesis
FdUMP = interferes with thymidine synthesis, preventing DNA synthesis
What kind of cancers is 5FU most commonly used for?
GI Cancers, stomach, colon, pancreas
Breast and Basal cell carcinoma
What is a cytidine analog used to treat acute leukemias, especially myelocytic leukemia?
Cytarabine
What are the common side effects of 5FU?
- n/v/d + anorexia
- Myelosuppression
How does Cytarabine work in preventing cell division?
Competes with Cytidine for phosphorylation and incorporation into DNA causing chain terminations
How are the side effects of Cytarabine different than 5FU?
- more significant myleosuppression, limits dosing
- neurotoxicity (not a side effect of 5FU)
What is a common purine analog used to prevent DNA synthesis?
Mercaptopurine, inhibits DNA/RNA synthesis by being converted to a ribonucleotide 6MP, becoming incorporated into the strands and disrupting.
What is the biggest concern when treating a patient with Mercaptopurine for ACUTE LEUKEMIAS?
There are populations of patients who have deficient TPMT that breaks down 6MP, which can cause severe bone marrow suppression. Patients should be tested for the defect prior to starting treatment.
What therapeutic is used to prevent the conversion of NTP to dNTP for integration into DNA?
Hydroxyurea - inhibits ribonucleotide reductase
causing the blocking of DNA synthesis
How does hydroxyurea effect the cell cycle and what is commonly used with this treatment?
S-specific treatment, arrests the cell in S-G1 interface. Used in conjugation with radiation therapy.
What is hydroxyurea commonly used to treat and what is the biggest concern of side effects?
Granulocytic Leukemia
Side effect: Hematopoietic Depression ( + GI symptoms)
How do the vinca alkaloids effect cancer cells?
M-phase specific, bind tubulin, inhibiting formation of microtubules and the mitotic spindle.
How are the side effects of Vinblastine and Vincristine different?
Vinblastine, STRONG bone marrow suppression and epithelial ulcerations
Vincristine, hairloss, neuromuscular abnormalities and neuropathy, LESS bone marrow suppression
Which Vinca alkaloid would be best for treating Hodgkin’s and Non-Hodgkin’s lymphoma?
Vinblastine, also treats Breast Cancer
What type of cancer is most commonly treated by Vincristine?
Acute Lymphocytic Leukemia
+ Wilms Tumor, Neuroblastoma, Lymphomas
What is the mechanism of action of taxanes and what phase do they work?
Taxanes enhance the stability of microtubules by binding the B-subunit, which blocks transition into M-phase. G2-M transition.
What drug can be used to sensitize cancer cells to be more susceptible to radiation?
Paclitaxel. This blocks transition into M-phase, which is when the cancer cells are most susceptible to radiation therapy.
Paclitaxel can be used with what other drugs for an additive effect?
Paclitaxel can interfere with DNA repair intensifying the effects of DNA damage caused by cisplatin / cyclophosphamide.
When are taxanes (Paclitaxel) typically used to treat cancers and what are the side effects?
Refractory ovarian and breast cancer.
Dose-Limiting leukopenia, peripheral neuropathy / myalgias
What are the various mechanisms of action of Doxorubicin?
- intercalating between DNA base pairs
- lipd peroxidation / free radical generation
- binds to DNA and topoisomerase
What kind of cells does Doxorubicin target and types of cancer?
Cycle-specific, phase nonspecific
- Hodgkins/Non-Lymphoma
- Breast/Ovarian
- Small-cell lung
What is a unique attribute of Doxorubicin that is uncommon among many anti-neoplastics?
Has anti-angiogenic properties
What is the biggest drawback of using Doxorubicin?
Cardiomyopathy, cumulative dose effect
+bone marrow suppression and GI
What is the key to the functionality to Bleomycin?
Iron activates the glycopeptides that bind DNA causing oxidative damage and double stranded breaks
What type of cells are targeted by Bleomycin?
Cells in G2 phase, Bleomycin = phase specific
Used to treat: Germ Cell Tumors of testes/ovaries
What is a unique side effect of Bleomycin?
Dose-related Pulmonary Toxicity, possibly fetal
Vesiculation of the skin
Skin Hyperpigmentation
*Minimal bone marrow and immune suppression
Which natural antibiotics selectively target cells in the G2 phase?
Bleomycin
Etoposide
What is the mechanism of Etoposide?
Stabilizes topoisomerase complexes, causing double stranded breaks
What are typical side effects and usages for Etoposide?
Wide range = Lymphomas, Acute leukemia, testicular
Side effects: Dose-limiting Leukopenia
What can be used to help limit neutropenia from cancer therapy?
Filgrastim - G-CSF, promotes progenitors of neutraphils to be released and expands the population.
Faster recovery from bone marrow suppression.
What is the antibody used to selectively target metastatic breast cancer cells? How?
20-30% of breast cancer cells overexpress the HER2 receptor, Trastuzumab binds the receptor preventing its function of promoting proliferation.
What are the adverse effects of using the Trastazumab antibodies?
Cardiomyopathy
Hypersensitivity
Infusion reactions, fever/chills, etc
What chemotherapy drugs use platinum complex to cross-link DNA?
Cisplatin - cycle specific, phase nonspecific
Carboplatin
Oxaliplatin
What is Cisplatin primarily used for treating?
Testicular and Ovarian cancers (in combination)
What are the main toxicities associated with Cisplatin?
- Nephrotoxicity
- Ototoxicity
- Neuropathy + Electrolyte imbalance
- Mild-Mod Myleosuppression
How are Carboplatin and Oxaliplatin different from Cisplatin?
Lower chance of the serious side effects from Cisplatin, but they have a more narrow spectrum.
Oxaliplatin is best at Colon Ca of the group
How does Procarbazine work at killing tumor cells?
Atypical alkylating agent, activated in vivo into a methylating agent damaging chromosomes. Does not cross react with other alkylating agents.
What does Procarbazine typically target?
Best for cells in G1 and S-phase
–Hodgkin’s Lymphoma
Side effects, myleosuppression + n/v
When are hormones used as chemotherapy agents?
When the cancers are dependent upon steroids for growth signals.
What are the various approaches to battling steroid dependent cancers?
- Opposite Steroid compounds
- Anti-Hormon compounds
What is a possible consequence of using hormonal therapy?
The tumor cells can stop responding to the hormones and switch to G0 making it more difficult to kill them.
When and how is prednisone used to treat cancers?
Binds to steroid receptors, depresses expression of growth factor genes inducing nucleases which can modulate lysis of the cell.
Primarily: Lymphomas and Leukemias + Breast Cancer
What are added effects of Prednisone?
- Anti-emetic
- Stimulates appetite
- Anti-inflammatory
Can cause: Immunosuppression, limited myleosuppression
How does Tamoxifen block breast cancer from growing?
Nonsteroidal anti-estrogen activated in vivo that competitively blocks estrogen receptors, typically preventing the cancer from growing, but once treatment stops they continue growing again.
Who can Tamoxifen be used in most effectively?
Advanced Post-Menopausal breast Cancer
Pre-menopausal metastatic breast cancer
–Prophylaxis for high risk patients–
What are the side effects from Tamoxifen?
Hot flashes
Fatigue
Muscle pain
N/V
How does the mechanism of Letrozole compare to Tamoxifen?
Letrozole is an irreversible aromatase inhibitor, preventing estrogen from being produced
Tamoxifen blocks the estrogen receptor.
Same side effects*
What kind of patients is Letrozole used for?
1st line treatment with post-menopausal advanced or metastatic breast cancer
How is the effectiveness of Letrozole compared to Tamoxifen?
Letrozole has a longer survival rate and longer time for the cancer to progress
How does Leuprolide lower the amount of testosterone?
Analog of GnRH, which stimulates LH/FSH causing testosterone to PEAK, then after 2-4 weeks lowers it to very low amount due to desensitizing the cells to GnRH
What and When is Leuprolide used to treat?
Advanced Hormonal responsive prostate cancer, usually 1st line therapy.
Side effects: Impotence and Hot flashes
What drug is typically used to treat metastatic prostate cancer?
Flutamide
How does Flutamide function in treating prostate cancer?
Anti-Androgen that blocks the androgen receptor, nonsteroidal.
What are unwanted side effects of Flutamide?
Gynecomastia
Hepatotoxicity
Impotency
What are ways in which resistance can occur against cancer therapies?
- Resting Cells, G0
- Toxic side effects, lowered doses
- Normal apoptosis triggers not functional
- Spontaneous mutations
- SELECTION
- Multi-Drug Resistance
How do therapies unknowingly select for resistant cells?
Tumors that are overgrown have many variations and when a chemotherapy drug is introduced there WILL be cells that are not effected and they are the only ones that continue to grow as the rest die from therapy.
How do strains develop that are multidrug resistant?
Mediated by ATP-pumps that prevent the influx of the toxic therapy drugs.
Problematic with: Vineristine, Doxorubicin, Bleomycin, Paclitaxel, and Etoposide
How can resistance be prevented?
Increasing doses of drug
Multidrug therapies
Co-administration to prevent resistance mechanisms
Recruit cells out of G0
Which common drugs lack bone marrow suppression?
Prednisone
Vincristine
Bleomycin
What are methods of combo therapies?
Sequential Blockage - same pathway multi targets
Concurrent inhibition - both paths
Complementary inhibition - product and synthesis inhibit
Rescue Cells - Leucovorin
Synchonization - get cells in one phase
Recruitment - entice cells to divide, then attack
