Spotlight pp Module 8 - Cell Cycle: G0, G1, S, and G2 Phases

• Chemotherapeutic drugs are used in advanced pharmacology for anesthesiology practice.
• The cell cycle includes phases like interphase and mitotic phase.
• Telophase and Cytokinesis are part of the cell cycle.
• Myosin II and Anaphase are related to chromosome movement during cell division.

The Cell Cycle

• Gap0 (G0) is a resting state where cells perform normal functions and may remain for long periods or permanently.
• Growth factors signal cells to progress through the cell cycle, and genetically mutated cells often enter G0 permanently.
• Cancer cells often gain control of growth signals, leading to unchecked multiplication.
• Gap1 (G1) is when cells are recruited for growth, increase in mass and organelles, and prepare for division as diploid cells.
• Synthesis (S) involves DNA duplication with continued cell growth, absence of errors leads to G2 phase, with DNA checkpoint.
• Errors in S phase lead to cellular repair or apoptosis.
• Gap2 (G2) is between DNA replication and mitosis, involving synthesis of additional proteins and cellular mitotic materials with continued cell growth with another DNA checkpoint.
• Mitosis (M) is where the cell divides into 2 daughter cells with equally distributed cellular contents.
• Mitosis includes 4 phases: prophase, prometaphase, metaphase, anaphase, and telophase.
• Prophase involves chromatin condensing into chromosomes and the nucleolus disappears.
• Prometaphase consists of nuclear membrane breaking down, kinetochore microtubules invading the nuclear space, and polar microtubules pushing centrosomes apart.
• Metaphase occurs when the nuclear membrane disappears, the spindle develops, and chromosomes align along the metaphase plate.
• Anaphase involves sister chromatids separating as spindle fibers lengthen, pulling chromosomes to opposite ends.
• Telophase includes chromosomes being sectioned off into distinct new nuclei where the genetic content is distributed equally.
• Cytokinesis begins, dividing the cytoplasm to form 2 new cells, starting after anaphase and finishing after telophase.
• Cancer is abnormal cell division with the ability to infiltrate and/or destroy normal body tissue.
• Malignant cells are characterized by a change in the activity of cell cycle regulators, genetic mutations (oncogenes), and avoid the need for growth factors for multiplication.
• Malignant cells can have problems encoding regulator proteins.

Malignant Cells and Tumors

• Malignant cells go through DNA changes or abnormalities promoting increased cell growth and division.
• These cells escape internal and external division controls and avoid programmed cell death.
• Additional mutations are required during tumor progression.
• Malignant tumors are groups of cells that divide excessively and have self-sufficient growth signaling, while being insensitive to anti-growth signaling.
• Malignant tumors can undergo metastasis and sustained angiogenesis, which is the growth of new blood vessels to provide oxygen and nutrients.

Role of P53 and Telomeres

• Tumor protein p53 is an important tumor suppressor, controlling the transition to S phase and is active at DNA damage or other unfavorable conditions.
• The P53 triggers production of cell-cycle inhibitors allowing activation of DNA repair enzymes.
• Cancer cells can be missing, have nonfunctional/mutant, or less active p53.
• Telomeres are DNA "end caps" that prevent the loss of genes at chromosome ends and appear as damaged DNA.
• Telomeres require protection from cellular DNA repair systems with special proteins.
• Shortening and loss of telomeres are related to cellular aging.
• Telomerase is an enzyme which extends telomeres, reversing telomere shortening.
• Telomerase is active in germ cells (sperm & ova), some adult stem cells, and cancer cells with shortened telomeres.
• Over multiple cell divisions telomeres are progressively shortened.
• In cancer cells, telomere replenishing by telomerase is prevelant, and they maintain a stable telomere length, and divide indefinitely.

Chemotherapy

• Chemotherapy involves a range of chemicals to eradicate malignant cells with the role of the immune system in identifying and eliminating foreign tumor cells.
• Contemporary therapy aims to harness the power of intrinsic immune system actions.
• Combo therapy refers to several antineoplastic drugs being used concurrently or in sequence, often working via different mechanisms, and targetting residual cells which have escaped therapy.

Chemotherapy Dosing

• Single doses are often not sufficient to kill all cells.
• The strategy uses largest tolerated doses, repetitive, and intermittent dosing.
• Chemotherapy targets cells actively undergoing DNA synthesis (S) or targets cell cycle specificity matched to the biology of the cancer treated.
• Toxicity manifestations are often related to rapidly dividing cell targets.

Anesthetic Considerations

• Preoperative evaluation includes assessment of chemotherapeutic regimen, labs (CBC, coagulation profiles, ABG, electrolytes, renal & hepatic function panels), assessing N/V, potential effects on anesthetics, ECG, and CXR.
• Assess inflammation of mucous membranes, chemo-induced peripheral neuropathy and PONV risk, and immunosuppression. Risk of CINV and PONV is considered weak.
• Aseptic techniques and prophylactic antibiotics are critical due to increased susceptibility to iatrogenic infections.

Akylating Agents

• Alkylating agents are non-cell cycle specific and work in all phases.
• The mechanism of action involves forming covalent alkyl bonds with nucleic acid (DNA) bases.
• They form intrastrand or interstrand bonds impairing cell DNA structure, inhibiting replication & transcription.
• Toxic to cells undergoing division.
• They include nitrogen Mustard Derivatives, Alkyl Sulfonates, Triazenes, and Nitrosoureas.
• Alkylating agents are indicated for hematologic malignancies and solid tumors.
• Adverse effects include bone marrow suppression (lymphocytopenia within 24 hrs), gonadal dysfunction (infertility, oligospermia, amenorrhea), and GI disturbances.
• Further adverse effects include CNS stimulants, N/V, muscle weakness, seizures, follicular damage (alopecia), and pulmonary issues (pneumonitis, pulmonary fibrosis).
• Alkylating agents may cause cardiotoxicity, several drugs has boxed warnings for hepatotoxicity, may cause new or secondary malignancy risk, phlebitis, and thrombophlebitis.
• Alkylating agents inhibit plasma cholinesterase activity, up to 2-3 weeks following alkylating therapy which increases risk for prolonged paralysis with succinylcholine.
• Nephropathy related to uric acid, may be prescribed allopurinol.
• Acquired resistance to alkylating therapy can develop through decreased cell permeability to drugs, increased production of competitive substances.

Platinum Complexes

• Platinum complexes are alkylating-like agents which cause damage in all phases of the cell cycle.
• The mechanism involves crosslinking adjacent or opposing bases to disrupt DNA, inhibiting essential cellular processes and inhibiting enzymes involved in replication, division.
• Platinum containing medications treat cancer and include Cisplatin, Carboplatin, and Oxaliplatin
• Cisplatin is indicated for solid tumors like lung, bladder, ovarian, uterine, testicular, and colorectal cancers.
• Cisplatin has boxed warnings for nephrotoxicity, ototoxicity, and peripheral neuropathy. -Cisplatin leads to decreased GFR, increased creatinine, renal tubular necrosis leading to acute renal failure, tinnitus and hearing loss and sensory neuropathies and loss of vibratory, position sensations.
• Additional adverse effects include myelosuppression (leukopenia, thrombocytopenia) and hypersensitivity reactions (facial edema, bronchoconstriction, tachycardia, HOTN).

Antimetabolites

• Antimetabolites are cell cycle specific.
• The mechanism of action involves preventing synthesis of complementary DNA, acting as false cellular nutrient, enzyme inhibition and mimicking nucleobases.
• Stops DNA replication and cell proliferation.
• Antimetabolites Include Folate Analogues (Methotrexate, Pemetrexed), Pyrimidine Analogues (Fluorouracil, Cytarabine, Capecitabine, Gemcitabine), Purine Analogues (Mercaptopurine, Thioguanine, Pentostatin, Cladribine, Hydroxyurea).
• Antimetabolites are used for hematologic issues such as leukemia, lymphoma, myelodysplastic syndrome, as well to treat psoriasis, rheumatoid arthritis, and solid tumors.
• Antimetabolites are "High Alert" medications where resistance to therapy is highly risky. Bone marrow suppression, leukopenia, thrombocytopenia, megaloblastic anemia, and pulmonary toxicity all adverse effects.
• Ulcerative stomatitis, diarrhea, hemorrhagic enteritis, intestinal perforation, nephrotoxicity requiring adequate hydration, as well hepatotoxicity and cirrhosis risk, are also adverse effects.
• Neurological adverse events include cerebellar syndrome (ataxia) and drowsiness, fatigue.
• Dermatitis, increased pigmentation, nail changes, alopecia, and photosensitivity are further adverse effects.

Topoisomerase Inhibitors

• Topoisomerase Inhibitors are Cell cycle specific.
• Inhibit topoisomerase I or topoisomerase II, most active during the S and early G2 phases.
• Mechanism is to inhibit uncoiling of DNA during replication where the DNA 'overwinds' itself until it breaks apart
• Anthracycline anti-tumor antibiotics also create free radicals to break DNA strands.
• Topoisomerase inhibitors act by cutting one and cutting both DNA strands which disables the DNA and causes cell death.

Anti-Tumor Antibiotics

• Anti-tumor antibiotics are products from streptomyces bacteria such as bleomycin, anthracyclines, doxorubicin, daunorubicin, and dactinomycin.
• Cell cycle non-specific, interfere with DNA replication.
• Includes Doxorubicin, Daunorubicin, Dactinomycin, Bleomycin, Etoposide, Topotecan, and Irinotecan.

Solid Tumor Indications

• Lung esp. small cell, ovarian, testicular, breast, thyroid, bladder, osteogenic, and sarcomas.

Hematologic Indications

• Leukemias and Lymphomas
• Cardiotoxicity from the anti-tumor antibiotic daunorubicin is an adverse effect.
• Free-radicals disrupt critical cardiac proteins and cell membrane components, and cause dose-related cardiomyopathy, increased serum troponin T, and CHF with impaired LV function
• Acute cardiomyopathy with arrhythmias and potentially a fatal form of cardiomyopathy associated with bronchitis & progressive ventricular failure.
• Dexrazoxane is a free radical scavenger that is protective against damage.

Anti-Tumor Pulmonary Toxicity

• Pulmonary toxicity is seen from free radical production in the presence of oxygen & iron or copper, and causes capillary endothelial & alveolar epithelial damage.
• This can manifest as pulmonary fibrosis, initial signs → dyspnea, hypoxemia, pneumonitis, pulmonary lesions (infiltrates develop), decreased pulmonary diffusion capacity.
• In anesthetic considerations, there are reports of postoperative respiratory failure in bleomycin treated patients, resulting in possible risk with excessive crystalloid administration.
• It's important to minimize fluids intraoperatively (consider using microdrip set) and consider use of colloids.
• Minimize inhaled oxygen concentrations, short periods of high concentrations may not be harmful.
• Risk factors consist of: preexisting pulmonary damage or renal dysfunction, bleomycin treatment within the previous 1 - 2 months.
• There can be Gl disturbances, inflammation, ulcerations of mucosa among other side effects such as alopecia.

Microtubule Inhibitors

• Microtubule inhibitors are cell cycle specific- Microtubules create cellular architecture and mediate cellular functions.
• Mechanism of action is the vinca alkaloids bind and inhibit microtubule formation, taxanes bind and inhibit microtubule breakdown.
• • Active in Mitosis phase fails & cell dies without replicating

Microtubule Indications

• Vinca Alkaloids: Vincristine, Vinblastine, Vinorelbine, Vindesine
• Taxanes:Paclitaxel, Docetaxel, Estramustine
• Indications: Breast, pediatric tumors like rhabdomyosarcoma/wilms tumor, Hematologic: leukemias,Solid tumors: Breast, Ovarian, Lung and MORE

Adverse Effects

• Pancytopenia, orthostatic HOTN, decreased GI motility(paralytic ileus), laryngeal nerve paralysis(hoarseness), urinary retention, dry mouth, tachycardia.
• Cardiac(Taxanes), neuromuscular. Cardiocascular effects are Dysrhytmias/Myocardial Ischemia/Edema/Effusion. Neuromuscular are Axonal Demyelination/Sensory Motor neuropathy/ areflexia/ parathesias/ Skeletal muscle pain/muscle weakness/ataxia.

Peripheral Neuropathy

• Evidence of safety with neuraxial, regional anesthesia is limited, there may be risk of worsening neuropathy.

Signal Transduction Modifiers-

• Cell Signaling and require normal cell interaction with growth factors for certain receptors.
• Hormonal treatment disrupts growth factor-receptor interactions, the growth receptor promotes and prevents growth.
• Examples: Suppression of Gonadotropin release by pituitary gland. Block estrogen production/receptors on CA cells, and antibody treatment target specific over-expressed.
• Hormones suppresses the function of hormones.
• Suppresses function of specific hormones slows and stops growth for hormone dependent cancers such as, Breast/ endometrial/ prostate.
• Broadly classified as: Sex hormones, antiestrogens, aromatase inhibitors, antiandrogens, and gonadotropin releasng hormone analogs.
• Antiestrogens are include tamoxifen, raloxifene, and Toremifene, Antiandrogens consist of Flutamide/bicalutamide/Nilutamide, and Monoclonal Bodies include Rituximab Trastuzumab,Cetuximab, Bevacizumab.

Hormone Side Effects

• Hormone Therapy comes with hormonal side that includes, throboembolic events,stroke or increased risk with CV disease. Also Hepatoxicity is an important factor.
• Gl Disturbance can occur(Anorexia, N/V.Diarrhea/weight gain, myalgia, arthralgia or fractures.
• Decreased libido, gynecomastia, hot flashes, vaginal irritation

Other Targeted Therapies

• Prevent infection which can lead to CA Development such as Hepatitis B, which leads to liver CA, or Cervical/ Penile/Anal, Throat etc.
• Antiproliferative, Antiangiogenic, immunomodulatory effects occur as well. Such as Thalidomide, lenalidomide, pomalidomide.

Chemotherapty Keypoints

• BLeomycin, Busulfan effects the lungs, while Doxorubicin effects the Heart, Vincristine causes Neurotoxicity and Cisplatin/ Carboplatin impact the Kindey.
• Some others such as the NITROSOUREAS has an effect on the central nervous system.
• A main target of side effects is the central nervous system which can cause effects such as nausea.