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pathopharm week 5 book notes Lehne: Chapter 101, 102, 103, pathopharm chapter 40: cancer
Terms in this set (271)
refers not to a single disorder, but rather to a large group of disorders that differ with respect to clinical presentation, aggressiveness, drug sensitivity, and prognosis.
sequence of growth stages that a cell moves through for mitosis and regeneration. In order for cells to undergo mitosis, the cell must go through stages G0, G1, G2, S, and M
Mature cell type is replaced by a different mature cell type
abnormal development or growth of cells, tissues, or organs
the new and abnormal development of cells that may be benign or malignant
Cancer cells are characterized by
immortality, persistent proliferation, invasive growth, and the ability to form metastases.
the cell is at rest and is not actively engaged in the cell cycle
A cancer-causing substance
Drugs such as _________ and _______ are both highly effective and much less toxic than traditional chemotherapeutic agents.
trastuzumab [Herceptin] (for breast cancer) and imatinib [Gleevec] (for chronic myeloid leukemia and GI stromal tumors)
cells enter the cell cycle and prepare for DNA replication. Proto-oncogenes are activated
DNA replication takes place
synthesis of structures occurs and the structures move to opposite poles in preparation for division into two separate cells. The 46 chromosomes reorganize as two separate sets of 23 chromosome pairs arranged at opposite poles. Two nuclear membranes develop around the two separate sets of 23 pairs
mitosis is completed and two daughter cells are created
Cancer can be treated with three basic modalities:
surgery, radiation therapy, and drug therapy.
genes that control cell replication
During the cell cycle, there are several checkpoints where DNA replication mechanisms can be stopped if
errors have occurred in the synthesis of cell parts before mitosis
- cells can undergo repair, recycling, or apoptosis if errors exist
Agents used for drug therapy fall into two main groups:
(1) cytotoxic agents and (2) noncytotoxic agents, such as hormones, immunomodulators, and targeted drugs.
cancer cells disregard checkpoints in the cell cycle
- cancer cells are constantly moving through the cell cycle stages
- cancer cells do not undergo scrutiny at these checkpoints and do not undergo apoptosis, or programmed degeneration
- cancer cells disregard the growth inhibitors released by neighboring cells
- as the cancer cells proliferate, they accumulate on top, around, and beside each other, take over boundaries of organs, crowd out normal cells, and may even break free and travel to distant body sites
as the cancer cells proliferate, they
accumulate on top, around, and beside each other, take over boundaries of organs, crowd out normal cells, and may even break free and travel to distant body sites
cell has become a certain cell type and will no longer divide
a process that stops additional cell growth when cells become crowded; cells become more and more anaplastic
the proliferation of the neoplasm within the tissue of origin
Mitotic rate vs. cellular death rate
Release of lytic enzymes
Decreased cell-to-cell adhesion
- our immune system constantly surveys the body for foreign substances or "non-self" antigens
- when a "non-self" antigen discovered, the immune system initiates an attack to destroy the invading substance
- with age, the strength of the immune system diminishes and tumor development becomes easier
refers to the extent that neoplastic cells resemble normal cells both structurally and functionally
- reversion to a more primitive cell type
- lack of differentiation
- indicates total cellular disorganization, abnormal cell appearance, and cell dysfunction
- well-differentiated; resembles tissue of origin
- progressive, slow
- cohesive cells, well-demarcated tumor
- no metastasis
- poorly differentiated; does not resemble tissue of origin
- erratic, slow to rapid
- invasive and infiltrating, surrounding normal tissue
- frequent metastasis
benign tumor classification and nomenclature
- named according to the tissues from which they arise and include the suffix "-oma"
- may progress to cancer
- Malignant tumors can be graded I through III
- Staging classifies the tumor according to size, invasiveness, and spread using this system
a benign, slow-growing fatty tumor located between the skin and the muscle layer
a malignant tumor that occurs in epithelial tissue
benign tumor of smooth muscle
malignant tumor of ductal or glandular tissue
benign tumor of the coverings of the brain (the meninges)
indicates that the cells are well-differentiated
indicates cells are moderately differentiated
malignant tumor classification and nomenclature
- named according to the tissues from which they arise
-- carcinoma: epithelial tissue
-- adenocarcinoma: from ductal or glandular tissue
-- sarcoma: mesenchymal tissue
-- lymphoma: lymphatic tissue
-- leukemia: blood-forming cells
indicates poorly differentiated or anaplastic cells
T is for
N is for
lymph node involvement
malignant tumor of mesenchymal tissue
M is for
metastasis to distant organs
malignant tumor of lymph nodes and lymph tissue
CML (chronic myelogenous leukemia)
- Clonal, neoplastic expansion of multipotent myeloid stem cell [myeloproliferative disease) -NEB cells
Etiology - Philadelphia chromosome - reciprocal translocation of long arms of 9 & 22
tumor cannot be assessed
AML (acute myelogenous leukemia)
mainly adults--myeloid; myeloid cells in bone marrow; associated with genetic alterations (blast cells occur); anemia, neutropenia, thrombocytopenia
malignant cancer of blood-forming cells
ALL (acute lymphocytic leukemia)
-B and T cells
-Mostly affects children
-85% cure rate
No evidence of primary tumor
CLL (chronic lymphocytic leukemia)
- Neoplastic transformation of lymphoid cells/B cells
- Both are well differentiated
malignant TRANSFORMATION of predominantly B-cells
carcinoma in situ (early cancer that has not spread to neighboring tissue)
progressive increase in tumor size or involvement
N stands for
Regional lymph nodes cannot be assessed
no evidence of regional node metastasis
increasing involvement of regional lymph nodes
No distant metastasis
gene mutations can be hereditary or sporadic, meaning that they were acquired during a person's lifetime
- two major classes of cancer genes: tumor suppressor genes and oncogenes
tumor suppressor genes
normally function to restrain cell growth. However, these genes can also become defective and lose the ability to inhibit cell growth and division, thus allowing cancer formation
tumor suppressor gene in cells that controls cellular apoptosis
natural programmed death of cells with damaged DNA
Cytotoxic anticancer drugs
injure normal tissue because these drugs lack selective toxicity
- act directly on cancer cells and healthy cells to produce cell death
genes that stimulate and regulate a cell's movement through the cell cycle, resulting in cellular growth and proliferation
- when mutated, they become oncogenes that stimulate constant, unrelenting cellular proliferation and cell cycling
- Certain malignancies are associated with cancer-inducing viruses. For any virus to live and propagate, it must insert it's genes into the host cell's genome.
- The host cell then becomes a manufacturer of the virus.
- In viral-induced cancer, the mechanisms of action differ among viruses; however, the mechanisms always involve activation of growth-promoting pathways or inhibition of tumor suppressors in infected cells
cervical cancer is associated with
Burkitt's lymphoma is associated with
such as hormones, immunomodulators, and targeted drugs
Hepatocellular carcinoma is associated with
the hepatitis B and C virus
The spread of cancer cells beyond their original site; cancer cells are suited for this task because they secrete vascular endothelial growth factor, a substance that gives them the capacity to develop new blood vessels
vascular endothelial growth factor
stimulates endothelial cells to multiply and restore endothelial lining
common metastatic sites for tumors
Neutropenia can be minimized by treatment with
granulocyte colony-stimulating factor (short-acting and long-acting forms) and granulocyte-macrophage colony-stimulating factor
—drugs that act on bone marrow to increase neutrophil production.
an unexpected pathological disorder provoked by the presence of cancer in the body
- common type involves the secretion of endocrine hormones unrelated to the cancer tumor
Surgery and irradiation are
the treatments of choice for most solid tumors.
a common paraneoplastic syndrome
- for unclear reasons, the body produces a parathyroid like hormone, which stimulates bone breakdown and calcium accumulation in the blood
granulocyte colony-stimulating factor
recombinant hematopoietic substance used to treat agranulocytic angina
- a progressive loss of body fat and lean body mass
- develops commonly in patients with cancer
- the patient suffers profound weakness, unintentional weight loss, fatigue, loss of appetite, and anemia
- the cause is theorized to originate with cytokines and mediators released by WBCs that are attacking the tumor
tumor cell markers
products of cancer cells such as hormones, enzymes, genes, antigens, or antibodies that are found in blood, spinal fluid, or urine
- some are celledomcofetal antigens because they are normally found during fetal development.
- examples of these antigens are carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP)
carcinoembryonic antigen (CEA)
Oncofetal glycoprotein antigen found in colonic adenocarcinoma and other cancers; also found in nonmalignant conditions.
a fetal protein that appears in the blood of adults with certain types of cancer
the leading cause of cancer-related death in both men and women throughout the world
- leading cause: cigarette smoking, 85% of patients with this condition had previously smoked
- other common causes: passive smoke, COPD, asbestos, radon, arsenic, genetics
- calculated in pack-years.
- this is the number of packs of cigarettes smoked multiplied by years smoked
- for example, a 60-year-old who smoked two packs of cigarettes per day since age 20 has an 80 pack-years (40 x 2) smoking history
types of lung cancer
Small cell lung cancer (SCLC)
Non-small cell lung cancer (NSCLC)
Non-small cell lung cancer (NSCLC)
makes up about 85% to 90% of all lung cancers; slow-growing.
Drugs are the treatment of choice for
disseminated cancers (leukemias, disseminated lymphomas, widespread metastases).
Small cell lung cancer (SCLC)
rapidly growing tumor that tends to metastasize quickly
the most common sites of metastasis of lung cancer are
the bones, liver, adrenal glands, pericardium, brain, and spinal cord
signs and symptoms of lung cancer
Lung sounds diminished over affected area
Percussion tones - dull over tumor
paraneoplastic ACTH in lung cancer
- a common paraneoplastic syndrome involves long tumor secretion of ACTH, which chemically resembles melanocyte-stimulating hormone
- melanocytes are often stimulated, giving the patient with lung cancer a tanned appearance
Stages of Lung Cancer
- range from 0 to 4
- a small, localized tumor, referred to as "in situ", is classified as stage 0
Stage 0 tumor
carcinoma in situ
Stage 1 tumor
a large tumor
Cell-cycle phase-specific drugs
are effective only during a specific phase of the cell cycle (e.g., S phase, M phase)
- they are active only against cells that are participating in the cell cycle
- Quiescent cells in G0 are spared
stage 3 tumor
keeps spreading but still in thorax
Regional: 20% survival at 5 years
stage 2 tumor
tumor with local lymph involvement
Drugs are also used as
adjuvants to surgery and irradiation to kill malignant cells that surgery and irradiation leave behind.
stage 4 tumor
has metastasized elsewhere
Distant metastases 2.2% survival at 5 years (97.8 die by 5 years)
2.01-4 with ulceration
>4 without ulceration
As with procarbazine and dacarbazine,
the active metabolites have alkylating activity. However, the precise mechanism of cell kill has not been established.
the second most common cancer in the United States after lung cancer; one in eight American women will suffer this condition in their lifetime
breast cancer risk factors
- Age over 50
- Prolonged reproductive life
- Hormone replacement therapy
- Obesity (estrogen storage in fat)
- Family history, mother, grandmother, sister
- Personal history
- First pregnancy after the age of 30
- Ashkenazi Jewish women
- BRCA1 and BRCA2
malignant tumor of the ovary; the fifth leading cause of cancer death in women
ovarian cancer risk factors
- Older age
- estrogen treatment
- family history
- Ashkenazi Jewish descent
- Family history
- BRCA1 or BRCA2
Malignant cell growth in the cervix; can be caused by HPV virus; the third most common cancer in women worldwide
- almost 100% of these cases test positive for HPV
cervical cancer risk factors
- History of sexually transmitted diseases
-Human papilloma virus (HPV) infection
-Early age at first sexual intercourse.
-Multiple sexual partners and/or partners who have multiple partners.
causes a persistent infection that progresses to cervical cancer
causes condylomata (genital warts) but does not cause cervical cancer
If a Pap Smear comes out abnormal,
a biopsy must be done. Dysplasia that is seen on a biopsy of the cervix is called cervical intraepithelial neoplasia (CIN).
The cell cycle has four major phases:
cervical intraepithelial neoplasia (CIN)
potentially cancerous abnormality of epithelial tissue of the cervix, graded according to the extent of abnormal cell formation:
CIN-1: mild dysplasia
CIN-2: moderate to marked dysplasia
CIN-3: severe dysplasia to carcinoma in situ
Diagnosis of cervical cancer
pap smears suggest invasive disease require further evaluation by colposcopy, colposcopic-directed biopsy, and endocervical curettage
scraping of tissue away from a surface of an organ; in this case, the surface of the cervix
a direct visual examination of the cervix where sites of abnormality can be biopsied
treatment of cervical cancer
- conization is a procedure that removes a wedge of tissue from the cervix
- if lymph nodes are involved, radiation therapy is needed.
- radical hysterectomy with bilateral pelvic lymphadenectomy combined external beam radiation with brachytherapy is needed for stage II, III, and IVA
- brachytherapy involves imbedding deposits of radioactive material in the cervical tissue
- for stage IVB, individualized therapy is used to provide pain relief. Radiation therapy is used for control of bleeding and pain, whereas systemic chemotherapy is used for metastatic disease
- approved by FDA 6/2006
- vaccine tested in females ages 9-26 only
- current recommendations include both men and women
- protects against the 4 most common types of HPV that cause cervical cancer
malignancy of the prostate gland
- the lifetime probability of developing this condition is 1 in 7; the probability increases with age
- develops in approximately 6/10 men aged 65 and older
- highest risk of developing and dying from this condition: African American men
- mainly develops in the glandular cells of the organ, so it is referred to as an adenocarcinoma
- initiated by carcinogenic mutations and it's growth is dependent on the male hormone testosterone
prostate cancer risk factors
Consumption of fat
High calcium intake
African American ethnicity
High alcohol intake
Exposure to Agent Orange and cadmium
signs and symptoms of prostate cancer
- early: no symptoms
- prostate gland enlargement can obstruct urine flow from the bladder, causing:
-- decreased force of stream
-- incomplete emptying of the bladder
-- patient needs to strain to get urine out
- frequency of urination
- back pain is often a late stage symptom because of vertebral bone metastasis
diagnosis of prostate cancer
- Digital rectal exam (DRE)
- PSA test
- the Gleason grading system ranks tumors histologically from 1 (most differentiated) to 5 (least differentiated and most likely to metastasize)
- the poorer the differentiation of the cancer cells, the worse the prognosis
High doses of methotrexate coupled with leucovorin rescue can
be used to treat methotrexate-resistant tumors.
- This technique can be potentially harmful in that failure to give sufficient leucovorin at the right time can be lethal.
cells prepare to synthesize DNA by synthesizing histones (proteins found in chromatin)
Treatment of prostate cancer
-Surgical removal of prostate
-Different types of radiation treatment
- a pyrimidine analog
- undergoes intracellular activation followed by incorporation into DNA, where it acts to inhibit DNA synthesis
cells synthesize DNA
low risk and active surveillance
- for low-risk disease, active surveillance or watchful waiting is increasingly recommended as prostate cancer is often a slow-growing disease that can be assessed over time
- the patient who is a candidate for active surveillance or watchful waiting is usually an elderly man older than age 75 who has other medical disorders
- a uracil analog
- undergoes intracellular activation, after which it inhibits thymidylate synthetase, thereby depriving cells of thymidylate needed to make DNA.
cells prepare for mitosis (division)
the presence of a malignant neoplasm in the large intestine; the second leading cause of death because of cancer
- beginning at age 50, all adults should have a colonoscopy performed every 10 years
used to treat cancer, not infections.
- fall into two major groups: anthracyclines (which damage the heart) and non-anthracyclines (which don't).
cell division (mitosis and cytokinesis)
- Non-cell cycle specific
> works by several mechanisms, including intercallation into DNA, inhibiting topoisomerase II, and creating free radical that damage cells
- Very effective but limited use due to cardiac toxicity and N/V
> High risk of severe tissue damage with extravasation
colon cancer usually starts as a polyp, a tumorous mass projects into the intestinal lumen
the resulting daughter cells may either enter G1 and repeat the cycle, or enter G0 and become mitotically dormant.
antitumor antibiotics that don't damage the heart
colorectal cancer risk factors
Low fiber in the diet
High amount of animal fat in the diet
Diets low in vitamin A, C, and E
Killing of cancer cells follows
To reduce the risk of heart failure while on doxorubicin,
the cumulative lifetime dose should be kept below 550 mg/m2
- The risk can be further reduced with dexrazoxane, a drug that helps protect the heart from doxorubicin.
- As a result, DNA polymerase and RNA polymerase are unable to use DNA as a template, and hence synthesis of DNA, RNA, and proteins is disrupted
symptoms of colorectal cancer
-Iron deficiency anemia
-Changes in bowel habits
-Melena (blood in the stool)
-Lower bowel cancers can present with hematochezia (rectal bleeding) and narrowing of stool caliber.
diagnosis of colorectal cancer
Stem cell transplantation
ratio of proliferating cells to resting cells
- tissues that have higher GF respond better to chemotherapy
at any given dose, drugs kill a constant percentage of malignant cells, regardless of how many cells are present
the use of drugs to treat a disease
Chemotherapy major toxicities
- bone marrow suppression
- digestive tract injury
- nausea, vomiting
- reproductive toxicity
Main Chemotherapy Classes
- Alkylating agents
- Platinum compounds
- Antineoplastic antibiotics
- Mitotic inhibitors
- Topoisomerase inhibitors
synthetic chemicals containing alkyl groups that attack DNA, causing strand breaks
- injure cells primarily by forming covalent bonds with DNA
- considered cell-cycle phase nonspecific because alkylation reactions can take place at any time during the cell cycle
used widely in cancer treatment damage DNA by creating intrastrand and interstrand cross-links. These compounds are cell cycle-nonspecific in action.
a type of anticancer drug, with a microbial origin, that blocks cell growth by interfering with DNA
Drugs that kill cells as the process of mitosis begins
chemicals that prevent cell division by inhibiting formation of substances necessary to make DNA; used in cancer chemotherapy
- analogs of important natural metabolites, and hence are able to disrupt critical metabolic processes, especially DNA replication
- Most are S-phase specific.
block the ligation step of the cell cycle, which generates DNA single- and double-strand breaks, leading to apoptotic cell death.
a collection of identical antibodies that interact with a single antigen site
group of drugs designed to reduce estrogen levels in a woman's body and stop the growth of cancer cells that depend on estrogen to live and grow
- block estrogen synthesis.
Adjunctive Chemo Drugs
- Monoclonal Antibodies
- Aromatase Inhibitors
substances that block the effects of testosterone. Cancer of the prostate depends on the male hormone testosterone for its growth. If the amount of testosterone is reduced it is possible to slow down or shrink the cancer.
bicalutamide, flutamide, nilutamide
a supportive care medication used to treat anemia caused by chemotherapy treatments
- does not treat cancer.
- Bone marrow stimulant
- It can help the body make white blood cells after receiving cancer medications.
- It can also improve survival in people who have been exposed to radiation.
used to stimulate the bone marrow to produce platelets in order to prevent low platelets that may be caused by chemotherapy
Over the course of chemotherapy, cancer cells often become
drug resistant, thereby decreasing the chance of success.
Hematopoietic Growth Factor
Actions - Stimulates growth of primitive megakaryocytic progenitors and increases the number of peripheral platelets.
Used for treatment of patients who have had a prior episode of thrombocytopenia after a cycle of cancer chemotherapy. In such patients it reduces the need for platelet transfusions.
Blood modifying agents
- Epoetin Alpha
- Interleukin 11
Breast cancer is treated with
surgery, radiation, cytotoxic drugs, and hormonal agents, of which there are two major groups: antiestrogens and aromatase inhibitors.
- Drugs that enhance immune function
- Used to restore normal function or to increase the ability of the immune system to eliminate harmful invaders
A group of hormones, including cortisol, released by the adrenal glands at times of stress
The purpose of intermittent chemotherapy is
to allow normal cells to repopulate between rounds of treatment
A substance that blocks certain kinases, some are more active in some types of cancer cells and blocking them may help keep the cancer cells from growing
- may also block the growth of new blood vessels that tumors need to grow
- some are used to treat cancer.
two major groups of hormonal agents:
antiestrogens and aromatase inhibitors
- For either group to work, the cancer must be ER positive.
If the cancer cells repopulate as fast as (or faster than) normal cells,
there will be no reduction in tumor burden with each round of treatment, and hence treatment will fail.
biological response modifiers
- Kinase Inhibitors
- CD20 Directed Antibodies
- Angiogenesis Inhibitors
The growth fraction of a tissue is defined as:
the ratio of proliferating cells to cells in G0
bind to estrogen receptor site on cancer cells thus blocking estrogen from going into the cancer cell. This interferes with cell growth and eventually leads to cell death.
Inhibit the stimulus for growth of blood vessels
Which tissues have a
tissues with a large percentage of proliferating cells and few cells in G0
CD20 monoclonal antibodies
are targeted against B-cell antigens, and are used in the treatment of B-cell Non-Hodgkin's lymphoma.
an antiestrogen approved for the prevention and treatment of breast cancer.
- Benefits derive from blocking ERs on tumor cells.
- The drug is not active against cancers that are ER negative.
- a prodrug that undergoes activation by hepatic CYP2D6.
Which tissues have a
tissues composed mostly of G0 cells
a GnRH agonist, has a biphasic mechanism of action
- During the initial phase, the drug stimulates release of interstitial cell-stimulating hormone (ICSH) from the pituitary and thereby increases production of testosterone by the testes.
- As a result, there may be a transient "flare" in prostate cancer symptoms.
- With continuous use, the drug suppresses ICSH release and thereby causes testosterone production to fall.
- Note: the drug does not decrease androgen production by the adrenal glands or by the prostate cancer itself.
Multidrug chemotherapy is
generally much more effective than single-drug therapy
Women using tamoxifen should not take
fluoxetine, paroxetine, or sertraline to suppress hot flashes.
- These SSRIs are strong inhibitors of CYP2D6 that can prevent tamoxifen activation, thereby increasing the risk of breast cancer recurrence.
- Safe alternatives include escitalopram and venlafaxine, which are not strong CYP2D6 inhibitors.
Why is multidrug chemotherapy more effective than single-drug therapy?
Because combination therapy can:
(1) suppress drug resistance
(2) increase cell kill
(3) reduce injury to normal cells (at any given level of anticancer effect).
By activating certain ERs, tamoxifen
increases the risk of endometrial cancer and thromboembolism.
Cytotoxic anticancer drugs are more toxic to cancers that have
a high growth fraction than to cancers that have a low growth fraction.
is more effective than tamoxifen and poses no risk of endometrial cancer
- an aromatase inhibitor
- is used to treat ER-positive breast cancer in postmenopausal women only.
- Benefits derive from preventing biosynthesis of estrogen from adrenal androgens.
- Adverse effects include musculoskeletal pain, osteoporosis, fractures, and (rarely) thromboembolism.
Why are cytotoxic anticancer drugs more toxic to cancers with a high growth fraction?
because cytotoxic anticancer drugs are more active against proliferating cells than against cells in G0.
an androgen receptor blocker used in combination with a GnRH agonist to treat prostate cancer.
- Benefits derive from (1) preventing cancer cells from undergoing increased stimulation during the initial phase of GnRH therapy and (2) blocking the effects of adrenal and prostatic androgens on prostate cells.
Ideally, the drugs used in combination therapy should have
(1) different mechanisms of action
(2) minimally overlapping toxicities
(3) good efficacy when used alone.
- the first angiogenesis inhibitor available, is a monoclonal antibody that binds with vascular endothelial growth factor (VEGF) and thereby prevents VEGF from promoting blood vessel formation
- By suppressing angiogenesis, it can inhibit further tumor growth but cannot directly kill existing tumor cells.
- can disturbances, and peripheral neuropathy.
- has clear benefits in colorectal cancer and nonsquamous non-small cell lung cancer, but not in breast cancer. Accordingly, approval for breast cancer has been withdrawn.
- can impair wound healing and can cause hypertension, hemorrhage, GI perforation, and thromboembolism.
Which cancers respond poorly to cytotoxic drugs?
the most common cancers—solid tumors of the breast, lung, prostate, colon, and rectum— because they have a low growth fraction
a proteasome inhibitor, reduces cell viability, increases apoptosis, and increases sensitivity to the lethal effects of radiation and traditional anticancer drugs
- can cause bone marrow suppression, Nausea, vomiting, diarrhea, constipation, fatigue, thrombocytopenia, neutropenia, anemia, peripheral neuropathy
Which cancers respond well to cytotoxic drugs?
only some rarer cancers—such as acute lymphocytic leukemia, Hodgkin's disease, and certain testicular cancers— because they have a high growth fraction
Bevacizumab has clear benefits in
colorectal cancer and nonsquamous non-small cell lung cancer, but not in breast cancer. Accordingly, approval for breast cancer has been withdrawn.
Glucocorticoids are toxic to
cancers of lymphoid origin, including acute and chronic lymphocytic leukemias, Hodgkin's disease, and non-Hodgkin's lymphomas.
- a prodrug that is converted to active metabolites in the body
- well absorbed following oral dosing, but undergoes rapid and extensive hepatic metabolism
- (Hexamethylmelamine) Altretamine [Hexalen], formerly known as hexamethylmelamine, is indicated for palliative therapy of persistent or recurrent ovarian cancer
When glucocorticoids are used acutely,
their toxicities are both mild and manageable.
When a neutropenic patient develops an infection,
immediate and vigorous intervention is required. Until lab reports on the identity and drug sensitivity of the infecting organism are available, empiric therapy with IV antibiotics should be instituted.
If neutropenia is substantial,
(absolute neutrophil count below 500/mm3), the next round of chemotherapy should be delayed
Where must neutrophil counts be monitored?
in patients taking myelosuppressive drugs
(toxicity to bone marrow) can reduce the number of neutrophils, platelets, and erythrocytes, thereby posing a risk for:
- infection (from loss of neutrophils)
- bleeding (from loss of platelets)
- anemia (from loss of erythrocytes).
As a rule, serious toxicity occurs to
normal tissues that have a high growth fraction (i.e., bone marrow, GI epithelium, hair follicles, sperm-forming cells).
chemotherapy effect on blood cells
loss of neutrophils and platelets is common
significant loss of erythrocytes relatively rare, but can happen with certain drugs (e.g., cisplatin).
To cure a patient of cancer, we must produce
100% cell kill, which is rare with chemotherapy alone.
Toxicity to normal tissues is
the major obstacle to successful therapy with cytotoxic anticancer drugs.
For drugs that act during a specific phase of the cell cycle,
selecting the right dosing schedule is critical to success.
Cancer chemotherapy has three possible benefits:
cure, palliation, and prolongation of useful life.
- For treatment to be justified, at least one of these benefits should be likely.
Anticancer drugs with vesicant properties can
cause severe local injury if the IV line through which they are being administered becomes extravasated.
Renal injury from hyperuricemia can be minimized by giving:
(2) prophylactic allopurinol (a drug that blocks uric acid formation)
(3) rasburicase (an enzyme that catalyzes uric acid degradation)
an enzyme that catalyzes uric acid degradation
a drug that blocks uric acid formation
Chemotherapy can cause hyperuricemia as a result of
DNA degradation secondary to massive cell death.
Anticancer drugs often injure
hair follicles, thereby causing alopecia (hair loss). Patients who want to wear a hairpiece should select one before hair loss occurs.
Nausea and vomiting can be reduced by
premedication with antiemetics.
- The combination of aprepitant, dexamethasone, and ondansetron is especially effective.
Many anticancer drugs cause moderate to severe
nausea and vomiting, in part by stimulating the chemoreceptor trigger zone.
Anticancer drugs can cause
- Irreversible male sterility.
-- accordingly, men undergoing chemotherapy should be counseled about possible sperm banking.
- Fetal malformation and death, primarily in the first trimester.
-- however, after 18 weeks of gestation, risk appears to be very low.
By injuring the epithelial lining of the Gl tract,
anticancer drugs often cause stomatitis and diarrhea.
Anemia can be managed with erythropoietin,
but only in patients who do not have myeloid malignancies (e.g., leukemia), and then only when the goal is palliation
Why must erythropoietin only be used when the goal is palliation?
erythropoietin shortens life in all cancer patients, and hence must not be used when the goal is cure or prolongation of life
granulocyte-macrophage colony-stimulating factor
acts on the one marrow to increase production of WBCs
Cell kill results primarily from
disruption of DNA synthesis
a folic acid analog, prevents conversion of folic acid to its active form.
the most widely used alkylating agent, is active against a broad spectrum of neoplastic diseases.
Because alkylation reactions can take place at any time during the cell cycle,
alkylating agents are considered cell-cycle phase nonspecific.
Bifunctional alkylating agents
form cross-links in DNA and thereby prevent DNA replication
- are more effective than monofunctional agents.
About 50% of the cytotoxic anticancer drugs are
phase specific; the rest are phase nonspecific.
Why are phase-nonspecific drugs more toxic to proliferating cells than to cells in G0?
(1) G0 cells often have time to repair drug-induced damage before it can result in significant harm and
(2) toxicity may not become manifest until the cells attempt to divide.
Although phase-nonspecific drugs can inflict biochemical lesions at any time during the cell cycle,
they are usually more toxic to proliferating cells than to cells in G0.
Cell-cycle phase-nonspecific drugs can
affect cells during any phase of the cell cycle, including G0.
To be effective, a phase-specific drug must
be present as neoplastic cells cycle through the phase in which the drug acts
- phase-specific drugs must be in the blood continuously over a long time.
Because of peripheral and central neurotoxicity,
patients should receive regular neurologic evaluations.
(tremors, ataxia, vertigo, hallucinations, seizures, depression) is less common.
Peripheral sensory neuropathy
- a result of damage to the nerves outside of the brain and spinal cord
- often causes weakness, numbness and pain, usually in your hands and feet
- is common
Nausea and vomiting can
also limit dosage.
The principal dose-limiting toxicity is
bone marrow suppression.
Cytotoxicity is limited primarily to leukemic lymphoblasts because
these cells are unable to manufacture their own asparagine as normal cells do
converts asparagine into aspartic acid and thereby deprives cells of asparagine needed to make proteins.
a planar molecule that intercalates DNA, thereby distorting DNA structure
- also disrupts the function of topoisomerase II, thereby causing strand breakage. This may be the primary mechanism of cell kill
- an anthracycline-type antitumor antibiotic.
a BRAF V600E kinase inhibitor indicated for patients with unresectable or metastatic melanoma with the BRAF V600E mutation
excreted in the urine.
can be considered the model of a successful targeted anticancer drug, being both highly effective and well tolerated
- a highly specific competitive inhibitor of BCR-ABL tyrosine kinase
- In patients with CML, the drug suppresses cell proliferation and promotes apoptosis.
Cells of chronic myeloid leukemia (CML) produce
an abnormal, continuously active enzyme—BCR-ABL tyrosine kinase—that activates regulatory proteins, which in turn inhibit apoptosis and stimulate excessive cell proliferation
BCR-ABL tyrosine kinase
activates regulatory proteins, which in turn inhibit apoptosis and stimulate excessive cell proliferation
- causes significant bone marrow suppression, but is relatively harmless to peripheral nerves.
- severe myelosuppression
- block assembly of the microtubules that move chromosomes during cell division. Accordingly, the drugs are M-phase specific.
- a monoclonal antibody that blocks the receptor portion of EGFR tyrosine kinase and thereby suppresses cell growth and promotes apoptosis.
- can cause severe infusion reactions and severe acne-like rash.
- is toxic to peripheral nerves
- does not significantly suppress bone marrow function
- because it spares bone marrow, it can be safely combined with drugs that suppress bone marrow.
- block assembly of the microtubules that move chromosomes during cell division. Accordingly, the drugs are M-phase specific.
EGFR (epidermal growth factor receptor)
(epidermal growth factor receptor) linked with tyrosine kinase, plays an important role in regulating cell proliferation.
a regulatory molecule found in certain normal cells and many cancer cells
Side effects of ADT include
erectile dysfunction, loss of libido, gynecomastia, reduced muscle mass, new-onset diabetes, myocardial infarction, and stroke.
Many targeted drugs are
- monoclonal antibodies directed at antigens found primarily on cancer cells
- small molecules that inhibit specific kinases that regulate cell proliferation
Androgen deprivation can be achieved with four types of drugs:
gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists, androgen receptor blockers, and CYP17 inhibitors.
Early (localized) prostate cancer is treated with
surgery or radiation, sometimes followed by ADT.
Advanced prostate cancer is treated with
androgen deprivation therapy (ADT), which can be achieved with castration and/or drugs.
Targeted anticancer drugs are
designed to bind with specific molecules (targets) that drive tumor growth.
- If the target molecules are found only (or mainly) on cancer cells, they should be able to arrest tumor growth while causing little or no injury to normal cells.
- The current reality is that most cause serious adverse effects.
If the target molecules are found only (or mainly) on cancer cells,
targeted drugs should be able to arrest tumor growth while causing little or no injury to normal cells
When breast cancer metastasizes to bone (the most common metastasis site),
it can cause hypercalcemia and fractures.
- Risk of fractures and hypocalcemia can be reduced with denosumab or zoledronate (a bisphosphonate).
patient-specific immunotherapy designed to stimulate an immune attack against prostate cancer cells. Each dose is custom made from the patient's own immune cells, collected by leukapheresis.
Trastuzumab and ado-trastuzumab
monoclonal antibodies used for breast cancer that bind HER2 receptors, causing inhibition of cell proliferation and immune-mediated cell death.
a first-in-class CYP17 inhibitor used to suppress androgen production in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel.
a molecule present in the cell membrane of normal and malignant B lymphocytes (B cells)
a monoclonal antibody that binds with CD20 and thereby initiates apoptosis and causes a lethal immune attack on B cells.
- The drug is indicated for B-cell non-Hodgkin's lymphoma and B-cell chronic lymphocytic leukemia
- can cause severe infusion-related hypersensitivity reactions
an antibody-drug conjugate (ADC), composed of brentuximab (a CD30-directed antibody) coupled with MMAE (a toxin that binds tubulin to cause mitotic arrest). The antibody serves only to deliver MMAE to cells that express CD30. MMAE does the actual damage.
a toxin that binds tubulin to cause mitotic arrest; does the actual damage.
a CD30-directed antibody
block growth of new blood vessels needed to supply solid tumors with oxygen and nutrients
- affect blood vessels rather than specific cancer cells, so they should be active against a wide variety of tumors
By suppressing angiogenesis, bevacizumab can
inhibit further tumor growth but cannot directly kill existing tumor cells.
multienzyme complexes that degrade intracellular proteins and thereby rid cells of proteins that are not currently needed, including proteins that regulate transcription, cell adhesion, apoptosis, and progression through the cell cycle.
When glucocorticoids are used long term,
they can cause many serious toxicities, including osteoporosis, adrenal insufficiency, increased susceptibility to infection, peptic ulcers, and diabetes.
can improve appetite and promote weight gain and may impart a generalized sense of well-being
- In addition to their use against lymphoid-derived cancers, they are used to manage complications of cancer and cancer therapy.
- toxic to cancers of lymphoid origin, including acute and chronic lymphocytic leukemias, Hodgkin's disease, and non-Hodgkin's lymphomas.
- Specific benefits include suppression of chemotherapy-induced nausea and vomiting, reduction of cerebral edema secondary to irradiation of the cranium, reduction of pain secondary to nerve compression or edema, and suppression of hypercalcemia in steroid-responsive tumors.
In addition to their use against lymphoid-derived cancers,
glucocorticoids are used to manage complications of cancer and cancer therapy.
Specific benefits of glucocorticoids include:
- suppression of chemotherapy-induced nausea and vomiting
- reduction of cerebral edema secondary to irradiation of the cranium
- reduction of pain secondary to nerve compression or edema
- suppression of hypercalcemia in steroid-responsive tumors.
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