Understanding Cancer, Tumors, and Metastasis

• Cancer refers to diseases characterized by uncontrolled division of abnormal cells, capable of invading other tissues due to DNA mutations.
• Metastasis is the spread of cancer cells to other parts of the body.
• A cyst is an abnormal sac or closed cavity filled with liquid or semisolid matter, it is not a tumor or cancer.
• A tumor, also known as a neoplasm, is a mass observed as a hard lump in the body.

Inflammatory Breast Cancer

• This cancer type does not typically present a tumor.
• Signs and symptoms include:
  • Sudden visible enlargement of breast.
  • Discoloration of breast skin.
  • Inward turning of nipple.
  • Tenderness and pain in affected breast.
  • Change in texture, resembling an orange peel.

Benign vs Malignant Tumors

• Benign tumors do not metastasize or invade surrounding tissues and are non-cancerous.
• Malignant tumors can invade and metastasize to all parts of the body, and are cancerous.

Steps of Metastasis

• Cancer cells melt collagen and connective tissue to enter the circulatory system.
• Intravasation: Invasion of cancer cells into the lymphatic and circulatory systems.
• Extravasation: Cancer cells latching onto other parts of the body.
• Angiogenesis: Growth of new blood vessels to supply nutrients to the aggressive cancer growth.
• A breast cancer cell that travels to the lungs remains a breast cancer cell, but metastatic.

Cancer Treatment Options

• Established treatments include surgery such as mastectomy, radiation therapy that uses radiation sources to directly hit the affected body part, chemotherapy that uses cytotoxic drugs and other drugs, hormone therapy, and stem cell transplant.

Goals of Chemotherapy

• Palliation: Alleviating symptoms and prolonging life.
• Cure: Complete eradication of cancer.
  • Early detection is key to curing cancer.
• Adjuvant: Chemotherapy as an additional treatment after initial treatment.
• Neoadjuvant: Chemotherapy as an additional treatment conducted first.

Common Side Effects of Chemotherapy

• Hair loss due to fast regeneration of hair follicles. Severity varies among patients.
• Loss of appetite due to effects on fast-growing cells in the GI tract.
• Nausea and vomiting due to effects on fast-growing cells in the GI tract.
• Diarrhea due to effects on fast-growing cells in the GI tract.
• Bone marrow suppression due to decreased production of rapidly dividing blood cells.
• Fatigue.

Classes of Chemotherapeutic Agents

• Cell-Cycle Specific Agents (CCSA): Target cancer cells within the cell cycle, actively dividing.
  • Phase Specific: Effective on a specific phase of the cell cycle.
  • Phase Non-Specific: Effective against cancer cells within the active cell cycle regardless of the phase.
• Cell-Cycle Non-Specific Agents: Target cancer cells at any phase of the cell cycle, including the G0 phase.

Chemotherapeutic Agents and Cell Cycle Phases

• M-Phase: Vinca Alkaloids.
• G1 Phase: Asparaginase and Prednisone.
• S Phase: Antimetabolites.
• G2 Phase: Bleomycin and Etoposide.
• Any phase except G0: Alkylating Agents, Antitumor Antibiotics, and Cisplatin.
• Any phase including G0: Nitrosoureas and Radiation.

Plant Alkaloids

• These are anti-cancer drugs derived from plants.
• Microtubules facilitate chromosome migration to opposite poles during cell division. They are building blocks of mitotic spindle that bridges chromosomes during anaphase.

Microtubule-Damaging Agents

• These are drugs such as Vinca Alkaloids (Vin-) and Taxanes (-taxel).

Vinca Alkaloids

• Isolated from Catharanthus roseus (Vinca rosea, periwinkle plant, chichirica)
• Agents include Vinblastine, Vincristine, Vindesine, and Vinorelbine.
• Mechanism of action: Binds to microtubules, promotes depolymerization (disassembly), and prevents the "rescue" of microtubules.
  • Vinblastine is used in testicular cancer.
    • Notable side effect: Bone marrow suppression.
    • Side effect mnemonic: vinBLASTine, blasts your bone.
  • Vincristine is used in Hodgkin's Lymphoma and Wilm's Tumor.
    • Notable side effect: Neurotoxicity or Peripheral Neuropathy.
    • Side effect mnemonic: vincristiNERVE.

Taxanes

• Extracted from Western yew (Taxus brevifolia) and European yew (Taxus baccata).
• Mechanism of action: Bind to and stabilize microtubules by enhancing tubulin polymerization. They block dynamic instability by stabilizing GDP-bound tubulin, forming weak polymers and clogged microtubules, inhibiting cancer cell division, leading to apoptosis.
  • Docetaxel is indicated for advanced breast cancer and prostate cancer.
  • Paclitaxel is used for ovarian cancer and advanced breast cancer.

Topoisomerase Inhibitors

• Two classes of drugs: Podophyllotoxins and Camptothecins.
• Topoisomerases are enzymes that break, unwind, and reseal tangled DNA strands, necessary for DNA replication and RNA transcription.

Podophyllotoxins

• Inhibit topoisomerase II, causing double-strand DNA breaks
  • Mnemonic: Dalawa ang P ni Podophyllotoxins kaya Topoisomerase II
• Plant source: Podophyllum peltatum (extracted from the root of mayapple).
  • Etoposide: Targets the G2 phase.
  • Teniposide: Targets the late S and early G2 phase.
• Etoposide indications: Monocytic leukemia, testicular cancer, lung carcinoma.
• Teniposide indication: Lymphomas.
• Notable side effects: Myelosuppression and Lymphoid System Toxicity.

Camptothecins

• Plant source: Camptotheca acuminata.
• Inhibit topoisomerase I
  • Mnemonic: Isa lang P ni Camptotecins kaya I.
  • Topotecan indication: Metastatic ovarian cancer and Cisplatin-resistant neoplasms.
• Irinotecan active metabolite: SN-38, which inhibits topoisomerase I.
  • Indication: Colon Rectal Cancer.
  • Notable side effect: Early and Late forms of Diarrhea.
    • Early form: Occurs within 24 hours, due to cholinergic effect, treated with Atropine.
    • Late form: Caused by SN-38 inducing mucosal damage with rate and electrolyte malabsorption, treated with Loperamide.
• UDP-glucuronosyl transferase 1A1 metabolizes SN-38 to its inactive form.
  • Contraindicated in Gilbert syndrome due to abnormalities with UDP-glucuronosyl transferase 1A1.
  • Gilbert syndrome symptoms: Jaundice appearance due to impaired bilirubin processing.
  • Toxicity: Patients with Gilbert Syndrome will experience an increase in Irinotecan toxicity as the active metabolite is not metabolized.

Anthracyclines

• Bacterial source: Streptomyces peucetius var caesius.
• Works during S Phase.
• Mechanism of action includes: Preventing topoisomerase from reattaching broken DNA ends and intercalation. Drug slices between DNA base pairs, causing additional DNA strand breaks.
  • Doxorubicin indication: Breast, ovarian, thyroid, and lung cancers; acute leukemia.
  • Daunorubicin and Idarubicin indication: Acute Leukemia.
• Adverse effects: Red or Orange Discoloration of Urine, Cardiotoxicity

Dactinomycin

• Mechanism of action: Intercalation, inserts between guanine-cytosine base pairs (Inhibits DNA and RNA synthesis). Works for Guanine and Cytosine Base Pairs
• Indication: Pediatric Cancers such as Wilms tumor and Kidney Cancer.
• Notable side effects: Radiation Recall and Potent Vesicant.

Plicamycin (formerly known as Mithramycin)

• Bacterial source: Streptomyces plicatus.
• Mechanism of action: Binds to DNA in presence of Mg2+ or other divalent cations, interrupts RNA synthesis.
• Needs Mg2+ or other divalent cations for it to induce effect.
• Plicamycin interrupts RNA synthesis
• Indication: Testicular Cancer.

Mitomycin

• Bacterial Source: Streptomyces caespitosus.
• Mechanism of action: Alkylation; Cross-linking of DNA strands, causing abnormal base pairing in Guanine.
• Converted to a metabolite that is responsible for the cross-linking
• Indication:
  • Second-line agent for metastatic colon cancer.
  • Cervical cancer (with Bleomycin and Vincristine).
  • Stomach, pancreas, and lung cancer (with Doxorubicin and 5-Fluorouracil).

Bleomycin

• Bacterial Source: Streptomyces verticillus.
• Mechanism of action: Causes DNA strand breaks due to oxidation of the DNA-bleomycin-Fe(II) complex, producing toxic free radicals which inhibit DNA synthesis.
• DNA-bleomycin-Fe(II) complex causes the strand break with Bleomycin through producing toxic free radicals.