Lecture 6: Cancer Chemotherapy II Flashcards
What is Multiple Myeloma?
A malignancy of plasma cells
What are 6 characteristics of multiple myeloma?
- Skull x-ray- “punched-out lesions”
- Very painful and usually older patients
- Monoclonal gammopathy
- Bence-Jones proteins in urine (Ab light chains) leading to renal insufficiency
- Bacterial infections due to low IgG production;
- Hypercalcemia
What are 4 key disposing factors of Hepatocellular carcinoma?
- Chronic Hepatitis B
- Chronic Hepatitis C
- Alcoholism
- Aflatoxin exposure (Mold)
What is the environmental cause of Mesothelioma and what can this increase the risk of?
- Asbestos induces mesothelioma directly
- increases the risk of Squamous cell carcinoma in conjunction with cigarette smoking
Mesothelial lining = Outside lining of the lung
Does smoking increase the risk of Mesothelioma?
NO
if you smoke and you get squamous cell carcinoma it does not increase your chance of getting mesothelioma
What are 2 antibiotics used as Chemotherapeutic agents?
Doxorubicin
DNA-bleomycin
What do antibiotics do to act as a chemotherapeutic agent?
Interacts with DNA and disruption of function, intercalates into DNA, inhibits topoisomerases, and generates free radicals to induce their effect
MOA of Doxorubicin as a chemotherapeutic agent (3)
Induces cytotoxicity due to:
- Membrane lipid peroxidation
- DNA-strand breaks
- Direct oxidation of purines and pyrimidines
uses CP450 to create free radicals and cause DNA break
What is a major side effect of doxorubicin/ daunorubicin?
Cardiotoxicity
MOA for bleomycin as a chemotherapeutic agent
causes DNA breaks, used to treat Hodgkin’s disease and testicular cancer, bleomycin-Fe3+ interacts with DNA to cause strand breaks.
creates a complex with oxidized Fe and creates free radicals which causes DNA break
What is a major side effect of Bleomycin?
Pulmonary fibrosis
Which drugs (5) are alkylating agents used as chemotherapeutic agents?
Cyclophosphamide
Carmustine and Lomustine
Decarbazine
Temoxolomide
How do Alkylating agents work as a chemotherapeutic agent? What is a major side effect that they can cause?
- Through Covalent interactions with key cellular component such as DNA, frequently used in combination with other drugs to treat cancers
- They are mutagenic and cause other cancers such as acute leukemia
Cyclophosphamide
1. Therapeutic use
2. MOA
3. Major toxicity
- Therapeutic use: non-Hodgkin’s lymphoma, breast cancer, and sarcomas
- MOA: its modification in the liver via CytochromeP450, to phosphoramide mustard is the major alkylating agent for DNA that is cytotoxic
- Major toxicity: hemorrhagic cystitis
Which alkylating agent(s) crosses the BBB?
Carmustine, Lomustine, Temozolomide
!!CLT CROSSES BBB!!
all used for treatment for brain tumors
temozolomide can also be used for melanoma therapies
Which 2 drugs are nitrosoureas?
Carmustine and Lomustine
Temozolomide is related to ____ and is metabolized into ____
Dacarbazine, MTIC
Dacarbazine
MOA?
Theraputic use?
Cross BBB?
MOA: (MTIC) which induces DNA methylation of guanine residues
Therapeutic use: Melanoma and Hodgkin’s lymphoma
Cross BBB: NOOO
Alkylating agents
What are the therapeutic uses for each?
Mechlororethamine
Melphalan
Busulfan
Chlorambucil
LY
Mechlorethamine- lymphoma treatment
Melphalan- multiple myeloma treatment
Busulfan- CML treatment
Chlorambucil- CLL treatment
LY
What are the microtubule inhibitors used as chemotherapeutic agents?
- Vincristine and Vinblastine
- Paclitaxel and Docetaxel
Vincristine and Vinblastine
–MOA?
–Vincristine therapeutic use
–Vinblastin therapeutic use
–MOA: microtubule depolymerizing drugs that block tumor cell proliferation by interfering with the cell cycle at the M phase.
–Vincristine: ALL, Wilm’s tumor, Ewing’s sarcoma, Hodgkin’s and Non-Hodgkin’s lymphoma
–Vinblastine: Hodgkin’s and Non-Hodgkin’s lymphoma
-stine=depoly
Paclitaxel and Docetaxel
–MOA?
–Paclitaxel therapeutic use (3)
–Docetaxel therapeutic use (4)
–MOA: microtubule stabilizing drugs that block tumor cell proliferation by interfering with the M phase of the cell cycle.
–Paclitaxel: ovarian, breast, and non-small cell lung cancer
–Docetaxel: prostate, breast, GI, and non-small cell lung cancers
Which drug(s) are platinum coordination complexes?
Cisplatin
Cisplatin
MOA?
Therapeutic use?
Side effects?
MOA: binds to guanine in DNA forming inter- and intra strand cross-links, these modifications block both DNA and RNA synthesis
Therapeutic use: used synergistically with radiation and other drugs to treat: ovarian, testicular, and bladder cancer
Side effects: severe nausea and vomiting, nephrotoxicity, ototoxicity
cross-links with strand and outside strand
Which drugs are Topoisomerase Inhibitors?
Topotecan
Etoposide
Topotecan and Etoposide MOA
Topoisomerase Inhibitors
Topoisomerases reduce torsional strain during DNA replication (S PHASE),
Blockade leads to double-strand breaks in DNA, inhibiting DNA replication
Theraputic use for
A. Topotecan
B. Etoposide
A. Topotecan- used to treat ovarian and small cell lung cancer, inhibits DNA replication
B. Etoposide- used to treat lung and testicular cancer
Which drugs are steroid hormones and their antagonists? These drugs are impt for which type of cancers?
- Tamoxifen
- Anastrozole and Letrozole
- Leuprolide
important in the therapy of breast and prostate cancer
What is Tamoxifen?
estrogen antagonist, and inhibits estrogen-dependent growth of breast cancer (in ER+ tumors)
What is Anastrozole and letrozole?
Aromatase inhibitors that block extra-adrenal synthesis of estrogen
Use: postmenopausal women with breast cancer
What is Leuprolide?
A GnRH analog which inhibits FSH and LH release, which reduce estrogen and testosterone levels (Prostate Cancer)
4 characteristics of Acute lymphoblastic leukemia (ALL)
- young patients
- Big cells=Leukemia blasts
- Cells are early in development
- Can rapidly kill pt (Survival has increased to 90% due to effective tx)
3 characteristics of Chronic lymphocytic leukemia (CLL)
- Elderly patients
- Cells stuck in late development
- Not as rapid-chronic and slow
Prostatic Adenocarcinoma
SX?
Lab?
Sx: Low back pain
Lab: Elevated PSA
3 Key Genetic Changes in Leukemias/ Lymphomas
MYC trabslocation->progrowth by incr cell division warburg metabolusm
MLL translocation and PML-RARA fusion gene->incr self-renewal
BCL2 translocation-> Prosurvival by decr apoptosis
What is Hodgkin’s Lymphoma?
spread contiguity with no extra nodal presentation
Has a big success With tx
What is Non-Hodgkin’s lymphoma?
spread noncontiguous, through multiple nodes, with Waldeyers ring, and Extra nodal presentation.
Tx more difficult
spreading crazy in lymph nodes=harder to treat
What is Burkitt’s Lymphoma?
Myc amplification
Lymphoma cells are latently infected with Epstein-Barr virus (EBV)
What is Follicular lymphoma?
Amplified expression of the anti-apoptotic gene, Bcl-2
What is Diffuse Large B-Cell Lymphoma?
Highly aggressive tumor with a marked growth rate; must be treated right away with chemotherapeutic regimens
Most cases show increased expression of !! Bcl6 !!, Bcl2 or Myc expression
What are the subtyes of Acute Myeloid Leukemia (AML)?
M3 and M5
What is the M3 subtype of AML?
M3 subtype: Promyelocytic leukemia
Stuck as Pro-myelocyte
Auer Rods
APC
What is the M5 subtype of AML?
M5 subtype: Monocytic leukemia
Stuck as Pro-MONOcyte
What is Acute Promyelocytic Leukemia (APL) caused by?
Chromosome 15-17 translocation causing RARα/PML fusion.
PML is related to cell death, when translocated it will disrupts self renewal
And they cannot differentiate (no seld-renewal)-> Grow Leukemic Blasts
What can treat (therapeutics) RARα/PML fusion?
All trans retinoic acid and arsenic trioxide
Trans retinoic Acid leads to differentiation (May not last)
Trans Retinoic Acid + Arsenic Trioxide = better chance
Hodgkin’s Disease plays a key role for what and induces what?
key role for malignant Reed-Sternberg cells and inducing
a proinflammatory and tissue injury environment
Why are malignant lymph nodes growing in Hodgkin’s disease?
because the accumulation of non-malignant cell types ( the environment creates mass that is similar to cancer mass aka, acts like a malignant mass but isn’t one)
Pro Inflammation + Mass that grows like a Cancer (Very unusual)
malignant cells are NOT causing damage
Key Multidrug Combinations that are effective Chemotherapeutic Regimens
What is R-CHOP?
Treats?
Rituximab
Cyclophosphamide
(H) Doxorubicin
(O) Vincristine
Prednisone
Treats: non-Hodgkin’s lymphoma- B-cell lineage
Key Multidrug Combinations that are effective Chemotherapeutic Regimens
What is MOPP?
Treats?
Mechlorethamine
(O) Vincristine
Procarbazine
Prednisone
Treats: Hodgkin’s disease
Key Multidrug Combinations that are effective Chemotherapeutic Regimens
What is ABVD?
Treats?
(A) Doxorubicin
Bleomycin
Vinblastine
Dacarbazine
Treats: Hodgkin’s disease
Key Multidrug Combinations that are effective Chemotherapeutic Regimens
What is BEACOPP?
Treats?
Bleomycin
Etoposide
(A) Doxorubicin
Cyclophosphamide
(O)Vincristine
Procarbazine
Prednisone
Treats: Advanced or recurrent Hodgkin’s disease
Key Multidrug Combinations that are effective Chemotherapeutic Regimens
What is Hyper-CVAD?
Treats?
Cyclophosphamide
Vincristine
(A) Doxorubicin
Dexamethasone
Methotrexate and Cytarabine also used in alternating cycles
Treats: pediatric ALL, administered into the CNS to prevent lymphoma spread there
What treats ALL of the B-Cell lineage?
Monoclonal antibodies directed to CD22
B-cell surface marker
Key Multidrug Combinations that are effective Chemotherapeutic Regimens
Which drugs are AC-T?
Treats?
(A) Doxorubicin
Cyclophosphamide
(T) Paclitaxel
administered in a sequential manner
Treats: early-stage breast cancer
What is malignant melanoma?
Local invasion and lymph node metastasis
Mutations in controlling cell proliferation and survival
Sometimes people regress and they wonder if it is due to the immune system
What is the treatment for Malignant melanoma?
Immunomodulatory antibodies- a developing therapy for solid tumors including melanoma
(ANTI PDLI is Tx)
Renal Cell Carcinoma/Clear Cell Carcinoma
SX?
Path?
Hx?
Sx: Flank pain and mass, hematuria
Path: Renal vein invasion
Hx: Von-Hippel Lindau syndrome
What are genetic alterations that cause the development of pancreatic adenocarcinoma
telomere shortening
Activation of: KRAS mutation
inactivation of: CDKN2A, TP53, SMAD4, BRAC2
What is Glioblastoma multiforme?
Can spread along white matter tracks and cross the midline through the corpus callosum
Explain Pulmonary and bone metastasis
It’s a metastasic carcinoma
- Renal cell CA goes to the lung
- Metastatic Breast CA goes to the bone
Doxorubucin falls under which class of chemotheraputics?
A. Alkylating agents
B. Anti-metabolites
C. Antibiotics
D. Microtubule inhibitors
C. Antibiotics
Which of the following drugs depolarize the microtubules?
A. Paclitaxel
B. Vinblastine
C. Docetaxel
D. None of the abive
B. Vinblastine
Which of the following cancers presents with cells latently infected with Epstein-Barr virus?
A. Multiple Myeloma
B. Follicular Lymphoma
C. Burkitt’s Lymphoma
D. Hodgkin’s Disease
C. Burkitt’s Lymphoma
Which of the following cannot cross the BBB to treat cancers finding sancturary in the CNS?
A. Carnustine
B. Lomustine
C. Temozolomide
D. Darcabazine
D. Darcabazine
Which of the following drugs is not part of the MOPP multi-drug therapy of Hodgkin’s?
A. Mechloroethamine
B. Vincristine
C. Procarbazine
D. Doxorubicin
D. Doxorubicin
