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DD & BL Unit 1 > Cancer & Anti Tumor Agents > Flashcards

Cancer & Anti Tumor Agents Flashcards

1
Q

Hypertrophy

A

Increase in cell size without increase in cell number

Physiologic example: uterus undergoes hypertrophy during pregnancy

Pathologic example: hypertrophic cardiomyopathy, hypertension

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2
Q

Hyperplasia

A

Increase in cell number, often driven by hormones/growth factors; may be associated with increased risk for neoplasia

Physiologic example: Mammary gland during puberty and pregnancy

Pathologic example: Endometrial hyperplasia, known risk factor for endometrial neoplasia

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3
Q

Metaplasia

A

Chance from one benign, differentiated cell type to another, usually in response to injury; may be associated with increased risk for neoplasm

Ex: Columnar to squamous metaplasia in the bronchus, due to smoking; known risk factor for bronchopulmonary neoplasia

Squamous to columnar metaplasia (“Barrett Esophagus”) in the esophagus, caused by acid reflux; known risk factor for esophageal neoplasia

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4
Q

Neoplasia

A

Progressive, unchecked increase in cell number either with or without invasion / metastasis (benign vs. malignant)

Generally a clonal, pathologic, irreversible process

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5
Q

Benign neoplasm - Characteristics

A

Do not invade or metastasize; cause injury locally by compression/interference in function of adjacent structures. May still be highly lethal, depending on location (i.e. brainstem = bad)

Often encapsulate
Necrosis is uncommon
Well differentiated (resemble tissue of origin)
Low ate of cell turnover
Cytologic uniformity
Boundary between tumor and adjacent tissue generally maintained

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6
Q

Malignant Neoplasm - Characteristics

A

Invade and metastasize; cause injury both by local tissue destruction as well as by distant dissemination and tissue destruction

Tumor necrosis is common as the tumor outgrows its own blood supply
Variable differentiation (grading)
High rate of cell turnover
Cytologic pleomorphism (cells look different from each other)
Loss of boundary between tumor and adjacent tissue (invasive)

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7
Q

Benign tumors of epithelial origin - nomenclature

A

ends in -oma

Ex: Adenoma (from glandular tissue), osteoma, fibroma

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8
Q

Malignant tumors - nomenclature

A

Epithelial - Carcinoma
Ex: Adenocarcinoma (glandular origin)

Mesenchymal - Sarcoma
Ex: Osteosarcoma

Lymphoma - lymph node origin

Leukemia - bone marrow origin

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9
Q

Clinical implications of benign neoplasia

A

Treated by excision/surgical resection alone
May recur
Generally do not progress to malignancy BUT, benign, but premalignant neoplasms exist - i.e. colonic adenoma

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10
Q

Dysplasia

A

Disordered cellular growth; in epithelia, dysplasia is the hallmark of early premalignant neoplasia

Characteristics include loss of cytologic uniformity, loss of normal histologic maturation, and loss of architectural orientation

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11
Q

What do pap smears do?

A

Sample cells looking for Cervical Intraepithelial Neoplasia (CIN) stages I - III

CIN I is low-grade dysplasia, usually driven by low-risk HPV

CIN II and III are high-grade dysplasia states usually driven by high-risk HPV and considered “pre-malignant”

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12
Q

Tumor Grade

A

The degree to which the tumor histologically resembles normal tissue

Low grade refers to more differentiation / greater resemblance to normal tissue

High grade refers to less differentiation / less resemblance to normal

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13
Q

TNM Classification of Cancer Staging

A 
T = Tumor 
N = Regional Lymph Nodes 
M = Distant Metastasis

Usually stages 1 through 4

Stages 1 and 2 involve locally invasive tumors without lymph node involvement or metastasis

Stage 3 involves lymph nodes

Stage 4 includes distant metastasis

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14
Q

Primary induction chemotherapy

A

Involves no surgery or radiation; often used for patients with advanced tumors/metastatic disease. Goals are usually palliative.

For a subset of patients, may be curative (lymphomas, pediatric ALL)

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15
Q

Neoadjuvant Chemotherapy

A

Use of chemotherapy in patients with localized cancer, before surgery or radiation; goals are to allow sparing of vital normal organs and kill micrometastatic disease that is locally present.

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16
Q

Adjuvant Chemotherapy

A

Use of chemotherapy in patients after local treatment such as surgery/radiation

Goal is to reduce the incidence of localized and systemic recurrence by killing metastatic tumor cells

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17
Q

Alkylating Agents

A

Mechanism: Produce inter-strand crosslinks in DNA

Resistance: Increased glutathione (GSH) interacts with alkylating agents, acting as a drug “sink” and conferring resistance; also, upregulation of DNA nucleotide excision repair machinery

Toxicity: Kills fast growing cells (hematopoietic, GI, gonads, alopecia)

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18
Q

Methotrexate (MTX)

A

Antimetabolite Class

Mechanism: Reversible, competitive inhibitor of dihydrofolate reductase (DHFR), required for synthesis of purine nucleotides; MTX is an analog of folic acid

Resistance: Increased expression of DHFR via gene amplification in extrachromosomal DNA pieces; expression of DHFR with reduced MTX binding affinity

Toxicity: General, affects rapidly dividing cells

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19
Q

Topoisomerase Interacting Agents

A

Mechanism: Stabilize the DNA/Topoisomerase complex after DNA cleavage but before ligation; causes DNA damage which is recognized by the cell, initiating apoptosis

Resistance: Increased drug efflux; mutations in topoisomerases that confer resistance to drug but do not alter enzymatic activity

Toxicity: Myelosuppression, cardiotoxicity, secondary malignancies

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20
Q

Vinca Alkaloids

A

Antimicrotubule Class

Mechanism: Binds to microtubule ends (tubulin), enhancing stability and depolymerization

Resistance: Increased efflux of drug conferring MDR, mutations in tubulin that alter binding

Toxicity: Targets rapidly dividing cells, particularly neurotoxicity

21
Q

Taxanes

A

Antimicrotubule Class

Mechanism: Bind to interior surface of microtubules, stablizing against depolymerization at both ends; prevents cell division, leading to apoptosis

Resistance: Drug efflux, conferring MDR; mutations in tubulin that prevent drug binding

Toxicity: Neuropathy, alopecia

22
Q

Hormonal Agents

A

I.e. Tamoxifen, Bicalutamide, Flutamide

Mechanism: Block hormone receptors, inhibiting their function as transcription factors

Resistance: Activation of the receptor by other mechanisms, mutations in receptors that alter the response to drug

Toxicities: Associated with altered steroid hormone signaling, i.e. hot flashes, decreased bone density, gynecomastia in men

23
Q

Inhibitors of Steroid Synthesis

A

Hormonal Agent Class

Aromatase inhibitors block synthesis of estrogen from androgens

GNRH analogues inhibit testosterone production

Toxicity: Hot flashes, decreased bone density in women, gynecomastia in men

24
Q

Antibodies

A

I.E. Herceptin (Anti-Her2), Avastin (Anti-VEGF for colon cancer)

Mechanism: Recognize and block cell surface receptors that are important in tumor cell growth; or, anti-tumor antibodies labeled with radioisotopes or chemotherapeutic drugs, delivering the drug locally, within the tumor microenvironment

25
Q

Kinase Inhibitors

A

Ex: Gleevec / Imatinib

Mechanism: Binds to the kinase active site, blocking the catalytic activity

Resistance: Expression of inhibitor-insensitive kinases via mutation selection, activation of secondary signaling pathways, over-expression of the kinase

May be possible to design a drug that works in resistant tumors, i.e. Dasatinib works in CML patients with mutated Bcr-Abl who are resistant to Gleevec

26
Q

Pathways of metastatic dissemination (3)

A
  1. Direct seeding of body cavities or surfaces
  2. Lymphatic spread
  3. Hematogenous spread
27
Q

Why do tumor cells metastasize?

A

Crowded cellular conditions within a tumor (lack of nutrients, hypoxia) provide positive selective pressure for cells that gain the ability to metastasize

28
Q

Steps of tumor invasion (4)

A
  1. Dissociation of tumor cells from one another - i.e. through the loss of cadherin
  2. Local degradation of the basement membrane and interstitial connective tissue by secreted proteolytic enzymes (i.e. MMPs)
  3. Changes in attachment of tumor cells to ECM proteins
  4. Migration through the degraded basement membranes by cellular locomotion, stimulated by the cleavage products of matrix molecules which have chemotactic and growth factor-like properties
29
Q

Epithelial to Mesenchymal Transition (EMT)

A

Inappropriate expression of mesenchymal tissue characteristics, allowing increased mobility and migration of cells

Often involves loss of cell-cell adhesion through down regulation of E-cadherin expression by hypermethylation of the promoter by transcriptional repressors (Zeb1, SNAIL, etc.)

Other changes include: loss of epithelial cell polarity and increased protease secretion

30
Q

Steps of the Metastatic Cascade

A
  1. Invasion
  2. Intravasation
  3. Extrvasation
  4. Colonization
31
Q

Intravasation

A

The mechanism by which tumor cells enter the bloodstream through the vascular wall; in circulation tumor cells are vulnerable to innate and adaptive immune defenses, and apoptosis stimulated by loss of adhesion (anoikis)

Tumor cells tend to aggregate in circulation; they may bind and activate platelets and coagulation factors, causing emboli

32
Q

Extravasation

A

Tumor cells adhere to the endothelium and move through the basement membrane into distant tissues

33
Q

“Seed and Soil” Theory

A

Interactions between tumor cells adhesion molecules and tissue-specific adhesion molecules expressed by the endothelial cells of the target organ - OR - interactions between tumor cell chemokine receptors and tissue-specific chemokines produced by the target organ

Dependent on a suitable microenvironment for tumor seeding and growth

34
Q

Dormancy

A

Prolonged survival of micrometastases without progression

35
Q

DNA Repair defects that predispose to cancer

A

Xeroderma Pigmentosum - defect in excision repair

Ataxia-telangiectasis - defect in dsDNA break repair

Fanconi’s anemia - defect in repair of X ray damage

36
Q

In situ

A

Refers to the pre-invasive stage of epithelial cancers (i.e. breast, skin, etc.)

Displays histological features of a malignant tumor but has not broken through the basement membrane yet

37
Q

Tumor microenvironment

A
  1. Mesoderm derived cells (i.e. fibroblasts, adipocytes, immune cells, endothelial cells)
  2. ECM (i.e. collagen)
  3. Soluble & matrix-associated growth factors, cytokines, proteases
38
Q

Mechanical Arrest Theory

A

Cells mechanically arrest in the first capillary bed they encounter once in the circulation

39
Q

Paraneoplastic Syndrome

A

Indirect effects of metastases occurring in 7-15% of patients; consequence of the presence of cancer, but not due to the local presence of cancer cells

I.e. ectopic hormone production, arthropathies, myopathies, neuropathies

40
Q

Ultimate causes of death in cancer

A 
Infection
Organ Failure
Thromboembolism
Hemorrhage
Emaciation
41
Q

Ames Test

A

Tests the mutagenicity of any given chemical

The chemical is added to bacterial agar containing media lacking histidine, His- bacteria, and liver enzymes; if a chemical is mutagenic, then large numbers of His+ clones arise on the plate

90% of carcinogens are mutagens in the Ames test

42
Q

Squamous Cell Carcinoma

A

Result from columnar to squamous metaplasia due to chronic smoking; cancer cells stain positive for keratin and can spread by lymphatics or via the blood

43
Q

Adenocarcinoma

A

May be seen in smokers or non smokers; cancer cells form primitive, gland-like structures and stain positive for mucin

44
Q

Large cell carcinoma

A

Undifferentiated, high grade lung cancer; anaplastic appearing cells do not produce either keratin or mucin

45
Q

Small cell carcinoma

A

High grade cancer without glandular or squamous differentiation; aggressive and widely metastatic, especially to the brain. Strongly linked to cigarette smoking.

46
Q

Pancreatic Cancer

A

Usually arises from moderately well differentiated adenocarcinomas; may form primitive gland-like structures and produce mucin. Synthesizes connective tissue stroma as it grows, called “desmoplasia” - feels hard as a result. Often metastatic by the time of diagnosis, explaining terrible prognosis (5% 5 year survival)

Whipple procedure: Removal of a large part of the pancreas, common bile duct, gall bladder, and duodenum.

47
Q

Colorectal Cancer

A

2nd leading cause of death among men and women. Mostly adenocarcinomas arising from the innermost, mucosal layer of the bowel wall arising from adenomatous polyps

48
Q

Prostate Cancer

A

Leading cause of cancer in men; malignant tumors often arise in the periphery of the gland and are palpable on DRE; benign prostatic hypertrophy (BPH) tends to enlarge the peri-urethral region and often produces problems with voiding

DD & BL Unit 1 (6 decks)

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