L27-28 Cancer Pharmacology: Principles

Basics Principles of Cancer Pharmacology

• The primary site refers to the original location where a tumor begins to grow
• Secondary sites refer to new additional locations where the tumor may spread and develop
• Metastasis refers to the spread of cancer, which usually occurs through the lymphatic or circulatory systems
• Solid tumors include cancers of the breast, lung, and prostate
• Solid tumors are stationary and can be felt if they are significantly large and accessible
• Diffuse tumors are cancers of the white blood cells, such as leukemias and Hodgkin's disease
• Diffuse tumors are not restricted to any one location
• Cancer treatment options vary depending on the type and location of the cancer
• Treatment options include surgery, radiation, and chemotherapy
• Surgery is the best method for solid tumors that are surgically accessible
• Radiation (X-ray treatment) is used after surgery to kill any cancer cells located in the area around where the tumor was located
• Chemotherapy is the primary treatment for diffuse tumors and is used post-surgery and irradiation of solid tumors to eliminate any metastasized cancer cells
• Chemotherapy is administered in cycles, which allow normal cells to recover faster than cancerous cells
• Remission refers to an inactive period when cancer cells are not actively dividing due to successful drug treatment
• Tumor markers include alpha FP for testicular cancer and PSA for prostate cancer

Log Kill Hypothesis

• Chemotherapy kills a constant fraction of tumor cells regardless of the initial tumor size
• Cancer cells follow logarithmic growth, and tumor growth follows an exponential pattern on a logarithmic scale
• Each treatment kills a constant percentage of cells
• Chemotherapy kills a constant fraction of tumor cells with each dose, so one dose killing 50% of the cells means the next dose will kill 50% of the remaining cells
• The implication is that a drug effective against a uniform tumor cell population should always kill a consistent proportion of cells, regardless of the starting tumor size
• Administering a drug capable of substantially reducing tumor size (i.e., 90%) can have a curative effect when repeated doses are administered
• This approach is particularly effective when cancer is detected early
• Chemotherapy is given in cycles, allowing normal cells to recover and minimizing damage while effectively destroying cancer cells

Cell Cycle

• Understanding the role of the cell cycle phases in the log-kill hypothesis is crucial in determining chemotherapy dosing and scheduling
• The cell cycle is divided into several different phases, which can vary in length depending on the type and growth rate of the cell
• Both normal and cancer cells reproduce through the cell cycle known as mitosis
• Mitosis is divided into different phases
• M Phase (Mitosis): when cells divide and form new cells
• G1 phase: the new cells are growing and synthesizing RNA and proteins
• S phase: the cells synthesize and duplicate DNA in preparation for the next cell division
• G2 phase: cells are preparing for mitosis
• G0 phase: cells are not actively dividing or resting phase
• Anticancer treatment: aimed at killing dividing cells

Cell cycle-specific and nonspecific phase inhibitors

• The activity of different classes of chemotherapy agents is optimal at different phases of the cell cycle, whereas other types of chemotherapy are cell-cycle non-specific
• Cell cycle nonspecific phase: Activity is not dependent upon the agent being available during a certain phase of the cell cycle
• Nonspecific phase may be administered over a shorter period of time, but may need a higher drug concentration (peak)
• Cell cycle-specific phase: Activity is primarily in one phase of the cell cycle, requiring longer administration periods
• Examples of different chemotherapy classes and specific agents:
  • Epipodophyllotoxin derivatives: Etoposide, Teniposide; Miscellaneous: Bleomycin
  • Topoisomerase-1 inhibitors: Topotecan, Irinotecan
  • Antimetabolites- Folate analogs: Methotrexate, Purine analogs: Cladribine, Fludarabine, Mercaptopurine, Pentostatin, Thioguanine, Pyrimidine analogs: Capecitabine, Cytarabine, Gemcitabine, Floxuridine, Fluorouracil
  • Miscellaneous Hydroxyurea
  • Taxanes- Docetaxel, Paclitaxel
  • Vinca alkaloids- Vinblastine, Vincristine, Vinorelbine
  • Cell Cycle Nonspecific Agents:
  • Alkylating agents: Chlorambucil, Cyclophosphamide, Busulfan, Ifosfamide, Mechlorethamine, Melphalan, Thiotepa
  • Anthracyclines antibiotics: Doxorubicin, Daunorubicin, Epirubicin, Idarubicin
  • Antitumor antibiotics: Dactinomycin, Mitomycin, Mitoxantrone
  • Nitrosoureas: Carmustine, Lomustine, Streptozocin
  • Platinum agents: Cisplatin, Carboplatin, Oxaliplatin
  • Miscellaneous: Altretamine, Dacarbazine, Procarbazine, Bendamustine
• Mitoxantrone can be cell cycle specific at certain concentrations (e.g., primarily causes G2 arrest at lower concentrations but can cause both S and G2 arrest at higher concentrations)

Hormone Therapy

• Medications that suppress endogenous hormones that drive the growth of certain tumor types (e.g., breast and prostate cancer)
• Selective estrogen receptor modulators (SERMs): Tamoxifen is used to treat hormone-receptor-positive breast cancer
• Aromatase inhibitors (Als): Anastrozole, letrozole, exemestane are used to treat hormone-receptor-positive breast cancer
• GnRH agonists: Leuprolide is used for testosterone suppression in prostate cancer and ovarian Suppression in breast cancer
• GnRH antagonists: Degarelix
• Selective androgen receptor antagonists: Flutamide, bicalutamide, enzalutamide, apalutamide
• Common side effects of hormone therapy include hot flashes and risk of thromboembolic events
• Hormone therapy is not effective for all types of cancer, and its effectiveness can vary depending on the individual case

Targeted Therapy

• Nomenclature: Small molecule inhibitors end in "-inib” / Monoclonal antibodies end in "-mab"
• Tyrosine kinase inhibitors- Small molecule inhibitors include-
  • Bind to the inactive form of BCR-ABL and prevent activation Imatinib, nilotinib, and dasatinib used to treat CML, ALL, and GISTs
  • EGFR inhibitors: Erlotinib, gefitinib, and afatinib; used in NSCLC
  • VEGF inhibitors: Sorafenib and sunitinib are used in HCC, RCC, and thyroid
• Monoclonal antibodies are given via infusion-
  • Anti-HER2: Trastuzumab and pertuzumab are used in breast cancer. Trastuzumab is also used in esophageal/gastric cancer
  • Anti-CD20: Rituximab and brentuximab target CD20 and are used in non-Hodgkin lymphoma, Hodgkin lymphoma, and CLL
  • Anti-VEGF: Bevacizumab and ramucirumab inhibit angiogenesis and are used in CRC, RCC, and NSCLC

Immunotherapy

• Checkpoint inhibitors boost the immune response against cancer by blocking signals that suppress it. They remove constraints on the immune system, enabling it to fight malignancy more effectively
• Checkpoint inhibitors are approved for multiple cancers (e.g., melanoma, RCC, NSCLC, HCC, and now many more tumor types)
• PD-1 inhibitors are the first class of drugs with FDA approval for a genetic pattern rather than an anatomical site
• Examples of immune checkpoint inhibitors by mechanism include-
  • Anti-PD1: Nivolumab, cemiplimab, and pembrolizumab
  • Anti-PD-L1: Atezolizumab, avelumab, and durvalumab.
  • Anti-CTLA4: Ipilimumab.

Antitumor Antibiotics

• All are cell cycle nonspecific, except bleomycin which is G2/M phase specific
  • Bleomycin :
    • Mechanism of Action: Induces free radical formation (superoxide and hydroxyl radicals) → breaks in DNA strands
    • Therapeutic Uses: Testicular cancer, Hodgkin lymphoma
    • Adverse Effects: Pulmonary fibrosis (fatal), skin hyperpigmentation, and is NOT myelosuppressive
  • Dactinomycin :
    • Mechanism of Action: Intercalates into DNA → prevents RNA synthesis
    • Therapeutic uses Wilms tumor, Ewing sarcoma, rhabdomyosarcoma
    • Adverse Effects: Myelosuppression
  • Anthracyclines Doxorubicin, daunorubicin, epirubicin, idarubicin:
    • Mechanism of Action:Induces free radical formation (super ion hydrogen peroxide) and intercalates into DNA → breaks in DNA strands → ↓ replication
    • Therapeutic Uses: Solid tumors, leukemias, lymphomas - Adverse Effects: Cardiotoxicity (a reduced left ventricular ejection fraction; often irreversible, prevented with dexrazoxane – an iron intracellular chelator), myelosuppression, and vesicant NOTE: Keep track of the lifetime cumulative doxorubicin dose for each patient (max dose: 450-550 mg/m²)

Antimetabolites

• All are S-phase specific except cladribine, which is cell cycle nonspecific
  • Thiopurines: Azathioprine, 6-mercaptopurine :
    • Mechanism of Action: Purine (thiol) analogs → ↓ de novo purine synthesis.
      • Azathioprine is converted into 6-MP, which is then activated by HGPRT.
    • Therapeutic Uses: Leukemias (ALL) Adverse Effects: Myelosuppression, hepatotoxicity, GI toxicities
  • Cladribine, pentostatin : - Mechanism of Action: Purine analogs unable to be processed by adenosine deaminase (ADA) → interfere with DNA synthesis. Therapeutic Uses Hairy cell leukemia - Adverse Effects Myelosuppression, neutropenia, teratogenic, peripheral neuropathy
  • Cytarabine :
    • Mechanism of Action: Pyrimidine analog (competes with cytosine) → DNA chain termination Inhibits DNA polymerase
    • Therapeutic Uses: Leukemias (ALL), lymphomas
    • Adverse effects Myelosuppression, hepatotoxicity, neurotoxicity, conjunctivitis (high dose)
  • 5-Fluorouracil:
    • Mechanism of Action: Pyrimidine analog bioactivated by 5- FdUMP (competes with uracil) → thymidylate synthase inhibition → ↓ dTMP → ↓ DNA synthesis; Capecitabine is a prodrug
  • Therapeutic Uses: Colon cancer, pancreatic cancer, basal cell carcinoma (topical)
    • Effects enhanced with the addition of leucovorin (because reduced folate coenzyme is required in the thymidylate synthetase inhibition)
  • Adverse Effects: Myelosuppression, Palmarplantar erythrodysesthesia (hand-foot syndrome), alopecia
  • Methotrexate:
    • Mechanism of Action: Folic acid analog that competitively inhibits dihydrofolate reductase →↓ dTMP →↓ DNA synthesis
    • Therapeutic Uses: Leukemias (ALL), lymphomas, choriocarcinoma, sarcomas. Cancer doses much higher than used for rheumatoid arthritis or psoriasis -Adverse Effects: Myelosuppression, hepatotoxicity, mucositis, pulmonary fibrosis, folate deficiency (teratogenic), nephrotoxicity
    • Overdose is reversible with leucovorin
• Hydroxyurea:
  • Mechanism of Action: Inhibits ribonucleotide reductase → ↓ DNA synthesis (S phase-specific)
  • Therapeutic Uses: Myeloproliferative disorders (e.g., CML, polycythemia vera)
  • Adverse Effects: Severe myelosuppression, megaloblastic anemia

Alkylating Agents

• All are cell cycle nonspecific
  • Nitrogen mustards: Cyclophosphamide, ifosfamide :
    • Mechanism of Action: Cross-links DNA strands interferes with DNA synthesis and cell replication; Require bioactivation by the liver - Therapeutic Uses: Solid tumors, leukemias, lymphomas
    • Adverse Effects: Myelosuppression, SIADH, Fanconi syndrome (ifosfamide), hemorrhagic cystitis which is prevented with Mesna
  • Nitrosoureas: Carmustine, lomustine: - Mechanism of Action: Cross-links DNA interferes with DNA synthesis and cell replication; Require bioactivation by the liver; Crosses blood-brain barrier - Therapeutic Uses: Brain tumors (including glioblastoma multiforme) - Adverse Effects: Pulmonary toxicity, CNS toxicity, impotence, infertility
  • Procarbazine - Mechanism of Action: unknown, Weak MAO inhibitor Therapeutic Uses: Brain tumors, Hodgkin lymphoma - Adverse Effects : Myelosuppression, pulmonary toxicity, disulfiram-like reaction (when taken in combination with ethanol – avoid alcohol intake) Note: can cause DNA mutation that can lead to “secondary malignancies"(e.g., leukemias and lymphoma)

Microtubule Inhibitors

• All are M-phase specific
  • Taxanes: Docetaxel, paclitaxel : - Mechanism of Action: Hyperstabilize polymerized microtubules → prevent mitotic spindle breakdown - Therapeutic Uses: Ovarian and breast cancer - Adverse Effects: Myelosuppression, neutropenia, neuropathy, hypersensitivity
• Vinca alkaloids: Vincristine, vinblastine: -Mechanism of Action: Bind B-tubulin and inhibit its polymerization into microtubules prevent mitotic spindle breakdown → disruption of microtubule assembly
  • Therapeutic Uses- Solid tumors, leukemias, lymphomas, Fatal only given via IV
  • Adverse Effects- Potent vesicants, Vincristine- peripheral sensory neuropathy, Vinblastine myelosuppression, less neurotoxicity

Platinum Compounds

• Cell cycle nonspecific
  • Cisplatin, carboplatin, oxaliplatin :
    • Mechanism of Action: Cross-links DNA → interfere with DNA synthesis and cell replication; Primarily binds to guanine bases in DNA strands, forming a platinum bridge
      • Therapeutic Uses: Solid tumors, lymphomas - Adverse Effects: Neurotoxicity, peripheral neuropathy (cumulative dose-related), ototoxicity

Topoisomerase Inhibitors

• All cause ↑ DNA degradation, resulting in cell cycle arrest in S and G2 phases -Camptothecin:Irinotecan, topotecan
  • Mechanism of Action: Inhibit topoisomerase I (an enzyme essential for the normal strand breakage and resealing of DNA strands) -Therapeutic Uses: Colon, ovarian, small cell lung cancer -Adverse Effects: Severe myelosuppression, diarrhea -Podophyllotoxins: Etoposide, teniposide -
  • Mechanism of Action: Inhibit topoisomerase II (an enzyme essential for the normal function and resealing of DNA strands) Therapeutic Uses: Testicular, small cell lung cancer, leukemia, lymphoma -Addverse Effects: Myelosuppression, alopecia

Hormones and Antagonists

• Selective estrogen receptor modulators (SERMS)- Tamoxifen: Antagonist in breast tissue/partial agonist in endometrium &bone ; prevention and treatment of breast cancer/prevents gynecomastia Adverse Effects: hot flashes /risk of thromboembolic events/endometrial cancer Raloxifene antagonist in breast tissue &uterus agonist at bone- risk reduction of invasive breast cancer- Hot flashes/Risk of thromboembolic events- No increased risk of endometrial cancer vs Tamoxifen
• Aromatase inhibitors -anastrozole ,letrozole exemastane- Inhibit peripheral conversion of angrogens to estrogren- used in Estrogen dependant breast cancer in post menopausal females- Can cause Myelosupression/osteoporosis/ischemic cardiovascular effects- is contraindicated in premenopausal/pregnant women -GnRH analogs: Leuprolide, goserelin, nafarelin, histrelin Mechanism of Action: Act as GnRH agonists when used in a pulsatile fashion, but also act as GnRH antagonists; will treat cancer if used in a continuous method. Therapeutic Uses: For prostate cancer- Adverse Effects: hypogonadism,, decreased libido -GnRH antagonists Degarelix ; Anti-androgen agent used for same cases in prostate - used as monotherapy due to not having issues from drug flare up effect
  • Selective Androgen Receptor antagonists: flutamide/bicalutamide- nonsteroidol , competitive testostrone antagonist -blocksinitial androgenic action- Causes Gyenocastia

Biological Response Modifiers - Target Therapies (Monoclonal Antibodies)

  - Human epithelial, growth factor,inhibitors. Inhibits growth factor for surface from biding promoting cell growth- can lead to Cardiotoxicity and heart failure

Rituximab: used in Non Hod Hodglknin lymphoma/CLL/ binds hematapoiteci, causing death -Antibody-Drug, Can be used to enable cytotoxic to enter cell

• Vascual, Endothelial used to promote growth with inhiobition in blood essles, to help treat cancer,, side effects include hemmohage,, impaired wound healling,, can lead to death,, not to give to patient befor surgery
• Multikinase inhiabitoer or reduces tumorangogiesnius used
• If EGFR over exoipressions = leads to sever,, skin toxicity or cardiac asst
• Goals for inhibitors to stop overgrowth with blocking programmed If PD-1, Tcells and Dysnfuction = it wil bloc moleculse which lead to destruction

Signal Transduction Inhibitors: Used fro tyrosine Kinases

• Used as small molecules tp prevent ATP bining and substrate phosporation
• Kinases are usedas family memebers and enzymes invilved in cell trsnduction

####### Drugs for inhibitors:

• BRAF: abnormal for kiness which melanoma. Used to treat philderphelai chomostones by bcr- Abl
• M EK" to Inhibit CELL, , to block or prevent proeteib,
• If 0, helps with Lung cancer used via genomic,. Alk to supress tyrosne and stop cancer in 5 percint
• Used with HeR2 used with breastc cencer in over exoepssions
• VEGF used fo Hepatocelua and thyroid as a cancer

Combination Chemotherapy Rationale

• Increase efficacy: Combining chemotherapeutic agents with different mechanisms of action can enhance treatment effectiveness
• Decrease risk of toxicity: Combining chemotherapeutic agents with different toxicities can reduce the risk of severe toxicity
• Minimizes cancer cell resistance to drugs: Combining drugs from different classes can minimize the likelihood of cancer cells developing resistance to individual drugs over time
• Target different phases of the cell cycle: Combination therapy with Cell Cycle-Specific (CCS) drugs effectively kills cancer cells

Chemotherapy Drug Combinations

• ABVD - Hodgkin lymphoma - Adriamycin (Doxorubicin) , Bleomycin, Vinblastine, Dacarbazine
• MOPP - Hodgkin lymphoma - Mustargen (Mustine), Oncovin (Vincristine), Procarbazine, Prednisone
• CHOP - Non-Hodgkin lymphoma - Cyclophosphamide, Hydroxydaunorubicin, Oncovin (Vincristine), Prednisone
• R-CHOP - Non-Hodgkin lymphoma - Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin (Vincristine), Prednisone
• FLOT - Stomach cancer- Fluorouracil, Leucovorin, Oxaliplatin, Docetaxel
• BEP - Testicular cancer- Bleomycin, Etoposide, Platinum
• TAC -localized breast cancerrisk of recurrence - Taxotere (Docetaxel), Adriamycin (Doxorubicin), Cyclophosphamide-
• CMF Fluorouracil – Breast cancer- Cyclophosphamide, Methotrexate

Chemotherapy Drug Resistance

• Efflux pumps: actively pump drugs out of the cells, reducing their effectiveness. Altered drug targets: genetic mutations or gene expression changes that alter chemotherapy drugs' target molecules. DNA repair mechanisms: cancer cells upregulate DNA repair mechanisms to repair chemotherapy induced dna damage Activation of survival pathways such as the pi3k/akt pathway which promotes cell survival and resistance to chemotherapy inducesd cell death Epigenetic Changes -changes in dna methlyation or histone modifcications contribute to drug resistance

Key Chemotoxicities

• Cisplatin/caboplatin cause Otoxicity vincristine cuases Peripheral neuopathy Bleotmycoim/bursulafn cuase Pulmonary fibrosos Doxorubicin/daunorubicin can cause cariiotixicotiy Cyclophosphamide cuases Hemmorhagi cysiti
• Side effects from chemo include: myelosuerpssion, neurotpenia , enieamn and also Gi related and alceocpua