IM-L0X-Principles of Cancer Tx-Unofficial

What are the main characteristics of cancer cells

Unregulated cell division, avoidance of cell death, tissue invasion, and metastasis

What is a benign neoplasm

Unregulated growth without tissue invasion or metastasis

What is a malignant neoplasm

Unregulated growth with tissue invasion and metastasis

How are epithelial-origin cancers called

Carcinomas

How are mesenchymal-origin cancers called

Sarcomas

What are hematopoietic-origin cancers called

Leukemias, lymphomas, and plasma cell dyscrasias (e.g., multiple myeloma)

What is cancer cell heterogeneity

Presence of diverse cell populations within a tumor due to varying extrinsic factors

What are examples of extrinsic factors influencing tumor heterogeneity

Stroma, infiltrating cells, cell-to-cell interactions, spatial orientation, secreted factors, oxygen and nutrient availability

Why does heterogeneity complicate cancer treatment

Some cell subsets may resist therapy and survive to proliferate

What are oncogenes

Genes that promote cell growth when altered, driving uncontrolled proliferation

How does cancer usually develop

Through a multistep process with multiple genetic abnormalities causing loss of proliferation and differentiation control

What cancer properties arise from genetic abnormalities

Tissue invasion, metastasis, and angiogenesis (formation of new blood vessels)

What safeguards do normal cells have against malignancy

DNA repair mechanisms and responses to extensive DNA damage

What are the phases of the cell cycle

G1 (growth/prep for DNA synthesis), S (DNA synthesis), G2 (prep for division), M (mitosis)

What are the recognizable steps in cancer progression

Hyperplasia → adenoma → dysplasia → carcinoma in situ → invasive cancer with metastasis

What components make up cancer tissue

Malignant cells, other cells, blood vessels, extracellular matrix, signaling molecules, and other microenvironmental factors

How do cancers behave compared to normal tissues

Like organs that lost specialized function and no longer respond to growth-limiting signals

What are the 4 main phases of the cell cycle

G1 (growth/prep for DNA synthesis), S (DNA synthesis), G2 (prep to divide), M (mitosis/cell division)

What is the 5th cell cycle phase called where the cell is quiescent

G0 phase

What regulates progression of a cell through the cell cycle

Checkpoints

Which checkpoint is regulated by cyclin B/cdc2 (MPF)

G2/M checkpoint

What is the role of the G2/M checkpoint

Prevent mitosis in the presence of damaged DNA

What cellular changes are caused by cyclin B/cdc2 activity

Chromosome condensation, nuclear membrane breakdown, spindle formation

What protein is known as the "guardian of the genome"

p53

What normally keeps p53 levels low in the cell

Rapid turnover via mdm2 targeting p53 for degradation

Which pathway activates p53 when DNA damage is detected

ATM pathway

What happens when ATM phosphorylates mdm2

It releases p53 from inhibition, allowing p53 to stop the cell cycle or trigger apoptosis

How can oncogenes activate p53 through p14ARF

p14ARF binds mdm2, freeing p53 to accumulate and halt the cell cycle or trigger apoptosis

Which checkpoint is most often disrupted in cancer growth

G1/S checkpoint

What protein plays a central role in the G1/S checkpoint and acts as a tumor suppressor

Retinoblastoma protein (Rb)

What happens to Rb when the cell is ready for S phase

Rb is phosphorylated, releasing E2F/DP1 to activate S phase genes

What happens if the cell is not ready for S phase

CDK inhibitors (p21, p16, p27) block progression

What is the role of the M (spindle) checkpoint

Ensures proper chromosome attachment to spindle before division

What happens if chromosomes are misaligned or number is abnormal at the spindle checkpoint

Cell death pathway is triggered to prevent aneuploidy

What genetic abnormality is a predominant feature in some tumors due to spindle checkpoint failure

Aneuploidy

What are examples of DNA repair errors that contribute to cancer

Mismatch repair, double/single strand breaks, base/nucleotide excision, translesional synthesis defects

What two general types of defects are found in tumors but usually not both together

Chromosome number defects and DNA repair pathway defects

What three main defects lead to cancer development

Abnormal cell cycle checkpoints, inadequate DNA repair, failure to preserve genome integrity

What does it mean when cancer mimics an organ

Attempts to regulate its own growth but lacks limits; both normal and cancer cells progress through the cell cycle

What is autonomous growth in cancer

Growth independent of normal regulation, measured by doubling time

What is doubling time in cancer

Mean time for tumor cells to divide; shorter doubling time = more aggressive tumor

What is Gompertzian growth in cancer

The characteristic growth curve of cancer cells with lag, log, and plateau phases

What happens in the lag phase of Gompertzian growth

Cells adapt, angiogenic switch is off, hypoxia induces HIF, then angiogenesis begins

What happens in the log phase of Gompertzian growth

Rapid cell growth with high proliferation

What happens in the plateau phase of Gompertzian growth

Growth slows; most cancers are clinically diagnosed here

What is an example of plateau phase cancer

A 50-year-old female with a 3 cm right breast mass, breast cancer in plateau phase

Which treatment is most effective during plateau phase

Surgery (eradicate cells) + chemotherapy as adjuvant

Which cancer treatment targets the log phase

Cytotoxic chemotherapy

What is the role of neoadjuvant therapy

Chemotherapy given before surgery

Does biopsy trigger cancer growth

No, biopsy does not trigger cancer growth

What is the primary goal of cancer therapy

Cure by eradicating cancer

What outcomes measure cancer treatment success

Overall survival and progression-free survival

What is the goal of palliation in cancer

Relieve symptoms, preserve quality of life, and minimize toxicities

What are loco-regional cancer treatments

Therapies targeting specific sites (e.g., surgery, radiation)

What are systemic cancer treatments

Cytotoxic chemotherapy, hormonal therapy, targeted therapy, immunologic therapy

What is the mechanism of cytotoxic chemotherapy

Small molecules (<1500 Da) targeting actively dividing cells in log phase

Which macromolecules are affected by cytotoxic agents

DNA, RNA, and proteins

How are cytotoxic agents classified

By activity relative to the cell cycle

What are phase non-specific agents in chemotherapy

Drugs effective regardless of cell cycle phase; require prolonged exposure

What are phase-specific agents in chemotherapy

Drugs effective only in certain cell cycle phases

What is the Fractional Cell Kill Hypothesis

Each cycle of chemotherapy kills the same proportion of tumor cells (3 log kill, 1 log regrowth principle).

In a tumor with 10¹⁰ cells, what happens after one cycle of chemotherapy

10³ cells die and 10⁷ remain, with regrowth of 10¹ during recovery (net cell kill per cycle = 10²).

Why are multiple cycles of chemotherapy required in the Fractional Cell Kill Hypothesis

Because not all tumor cells are killed in a single cycle.

What is natural resistance in cancer therapy

Initial non-responsiveness of a tumor to a given drug.

What is acquired resistance in cancer therapy

Resistance that emerges after an initially successful treatment.

What is the Goldie-Coldman Hypothesis

Resistance arises due to somatic mutations as tumor cell population increases, leading to phenotypic variants.

What are the mechanisms of resistance based on cell kinetics

Effects due to different growth fractions in the Gompertzian growth curve.

What are biochemical mechanisms of resistance in cancer

Inability to convert drug to active form, presence of blocking substances, or multidrug resistance (MDR).

What is multidrug resistance (MDR) in cancer

Resistance to a drug, its class, and several unrelated agents.

How can biochemical resistance be managed

Use combination chemotherapy, biologic response modifiers, rescue agents, autologous bone marrow transplantation, and blood cell growth factors (G-CSF, GM-CSF).

What are pharmacologic mechanisms of resistance

Poor absorption, increased excretion/catabolism, drug interactions, or poor transport to tumor cells.

Why should permission be asked if a patient wants to take herbal agents during chemotherapy

They may increase catabolism and alter drug metabolism.

How can pharmacologic resistance be overcome

Use combination chemotherapy to bypass poor absorption or transport issues.

What are the goals of combination chemotherapy

Prevent resistant clones, kill resting and dividing cells, enhance biochemical effects, access sanctuary sites, and rescue normal cells.

What are the mechanisms of hormonal therapy in cancer treatment

Additive (corticosteroids), Ablative (castration: oophorectomy, orchiectomy), Competitive (antiestrogens, antiprogestins, antiandrogens), Inhibitive (aromatase inhibitors, LH-RH analogues)

What is the role of steroid hormones in cancer therapy

Used in combination regimens, brain metastasis, spinal cord compression, cancer pain, prevention of chemotherapy-induced nausea/vomiting, appetite stimulation

How are glucocorticoids used in cancer treatment

Given in pulsed high doses in leukemias and lymphomas

What are the side effects of glucocorticoids in cancer therapy

Cushing’s syndrome, adrenal suppression after withdrawal, infections (eg Pneumocystis)

What is the mechanism of action of Tamoxifen

Partial estrogen receptor antagonist with 10-fold greater antitumor activity in ER+ breast cancer

What are the side effects of Tamoxifen

Increased risk of thromboembolic events and small increased incidence of endometrial cancer

What is the function of aromatase in cancer biology

Catalyzes estrogen formation by converting testosterone to estradiol in ovary, adipose tissue, and tumor cells

What are the types of aromatase inhibitors

Irreversible steroid analogues (exemestane), reversible inhibitors (anastrozole, letrozole)

What is the mechanism of biologic therapy in cancer

Targets molecular characteristics unique to cancer cells important for malignant phenotype

What are common mechanisms of resistance to cancer treatment

Defects in uptake/metabolism/export, increased target expression, loss of apoptosis, alternate pathway activation

What is the major hematologic side effect of cytotoxic chemotherapy

Myelosuppression affecting bone marrow function

When does maximal neutropenia occur after chemotherapy

6–14 days after conventional doses of anthracyclines, antifolates, and antimetabolites

What are the types of chemotherapy-induced nausea and vomiting

Acute (<24h), delayed (≥24h), anticipatory

What are the features of chemotherapy-induced diarrhea

Immediate or delayed (48–72h); requires hydration and electrolyte replacement

What is mucositis in chemotherapy

Inflammation/ulceration of oral and anal mucosa due to damage to proliferating squamous epithelial cells

Which agents most commonly cause near-total alopecia

Anthracyclines, alkylating agents, topoisomerase inhibitors

Which agents cause variable alopecia

Antimetabolites

What causes gonadal dysfunction in cancer treatment

Alkylating agents and topoisomerase regimens causing cessation of ovulation and azoospermia

What is the typical outcome of gonadal dysfunction after alkylating therapy

Amenorrhea with anovulation