Cancer & Anti Tumor Agents Flashcards
Hypertrophy
Increase in cell size without increase in cell number
Physiologic example: uterus undergoes hypertrophy during pregnancy
Pathologic example: hypertrophic cardiomyopathy, hypertension
Hyperplasia
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
Metaplasia
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
Neoplasia
Progressive, unchecked increase in cell number either with or without invasion / metastasis (benign vs. malignant)
Generally a clonal, pathologic, irreversible process
Benign neoplasm - Characteristics
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
Malignant Neoplasm - Characteristics
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)
Benign tumors of epithelial origin - nomenclature
ends in -oma
Ex: Adenoma (from glandular tissue), osteoma, fibroma
Malignant tumors - nomenclature
Epithelial - Carcinoma
Ex: Adenocarcinoma (glandular origin)
Mesenchymal - Sarcoma
Ex: Osteosarcoma
Lymphoma - lymph node origin
Leukemia - bone marrow origin
Clinical implications of benign neoplasia
Treated by excision/surgical resection alone
May recur
Generally do not progress to malignancy BUT, benign, but premalignant neoplasms exist - i.e. colonic adenoma
Dysplasia
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
What do pap smears do?
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”
Tumor Grade
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
TNM Classification of Cancer Staging
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
Primary induction chemotherapy
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)
Neoadjuvant Chemotherapy
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.
Adjuvant Chemotherapy
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
Alkylating Agents
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)
Methotrexate (MTX)
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
Topoisomerase Interacting Agents
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
Vinca Alkaloids
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
Taxanes
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
Hormonal Agents
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
Inhibitors of Steroid Synthesis
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
Antibodies
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
Kinase Inhibitors
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
Pathways of metastatic dissemination (3)
- Direct seeding of body cavities or surfaces
- Lymphatic spread
- Hematogenous spread
Why do tumor cells metastasize?
Crowded cellular conditions within a tumor (lack of nutrients, hypoxia) provide positive selective pressure for cells that gain the ability to metastasize
Steps of tumor invasion (4)
- Dissociation of tumor cells from one another - i.e. through the loss of cadherin
- Local degradation of the basement membrane and interstitial connective tissue by secreted proteolytic enzymes (i.e. MMPs)
- Changes in attachment of tumor cells to ECM proteins
- 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
Epithelial to Mesenchymal Transition (EMT)
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
Steps of the Metastatic Cascade
- Invasion
- Intravasation
- Extrvasation
- Colonization
Intravasation
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
Extravasation
Tumor cells adhere to the endothelium and move through the basement membrane into distant tissues
“Seed and Soil” Theory
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
Dormancy
Prolonged survival of micrometastases without progression
DNA Repair defects that predispose to cancer
Xeroderma Pigmentosum - defect in excision repair
Ataxia-telangiectasis - defect in dsDNA break repair
Fanconi’s anemia - defect in repair of X ray damage
In situ
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
Tumor microenvironment
- Mesoderm derived cells (i.e. fibroblasts, adipocytes, immune cells, endothelial cells)
- ECM (i.e. collagen)
- Soluble & matrix-associated growth factors, cytokines, proteases
Mechanical Arrest Theory
Cells mechanically arrest in the first capillary bed they encounter once in the circulation
Paraneoplastic Syndrome
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
Ultimate causes of death in cancer
Infection Organ Failure Thromboembolism Hemorrhage Emaciation
Ames Test
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
Squamous Cell Carcinoma
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
Adenocarcinoma
May be seen in smokers or non smokers; cancer cells form primitive, gland-like structures and stain positive for mucin
Large cell carcinoma
Undifferentiated, high grade lung cancer; anaplastic appearing cells do not produce either keratin or mucin
Small cell carcinoma
High grade cancer without glandular or squamous differentiation; aggressive and widely metastatic, especially to the brain. Strongly linked to cigarette smoking.
Pancreatic Cancer
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.
Colorectal Cancer
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
Prostate Cancer
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
