Cell Cycle: G0, G1, and S Phases

• The cell cycle consists of four major phases: G1, S, G2, and M, with G0 being a resting phase outside the main cycle.
• Interphase includes G1, S, and G2 phases, where the cell spends the majority of its time, doubling cytoplasm and synthesizing DNA.
• The typical duration for a human cell to complete the cell cycle is approximately 24 hours.

G0 Phase

• A non-dividing or resting state where cells exit the cell cycle and perform normal functions.
• Cells in G0 can remain there for extended periods or permanently, like neurons or liver cells.
• Growth factors signal cells to leave G0 and enter the cell cycle.
• Mutations can cause cells to enter a permanent G0 state, preventing replication.
• Cancer cells often disregard growth signals and bypass G0 to replicate unchecked.

G1 Phase

• The phase immediately before DNA synthesis, where the cell grows and increases in mass.
• Organelles form, and the cell is diploid, containing two sets of chromosomes.

S Phase

• DNA synthesis and chromosome duplication occur.
• The cell continues to grow.
• A checkpoint exists to detect and repair errors.
• Apoptosis occurs if errors are irreparable.

G2 Phase

• Occurs between DNA replication and the start of mitosis.
• The cell continues to grow and produce necessary molecular building blocks.
• Another DNA checkpoint ensures there are no problems before mitosis.

Mitosis

• The cell divides into two daughter cells with equal distribution of contents.
• Prophase: Chromatin condenses into chromosomes, which migrate to the cell's center, and the nuclear envelope breaks down.
• Metaphase: The nuclear membrane disappears, a spindle develops, and chromosomes align.
• Anaphase: Sister chromatids separate, and spindle fibers lengthen the cell.
• Telophase: Chromosomes are sectioned into two new nuclei, and genetic content is equally distributed.
• Cytokinesis: The cytoplasm divides, forming two new cells, starting after anaphase and finishing after telophase.

Cancer

• Malignant cells divide rapidly due to problems with division and synthesis.
• There are issues with the normal regulatory functions during the cell cycle.
• Genetic mutations, called oncogenes, can occur.
• Malignant cells multiply without growth factors and bypass resting phases.
• Cancer is defined as uncontrolled cell division that can infiltrate and destroy normal tissue.

Malignant Cells Mutations

• Changes in DNA promote increased growth and division.
• Cells escape internal and external division controls.
• Programmed cell death (apoptosis) is avoided.
• Additional mutations are often needed for tumor progression.

Tumors:

• Are groups of cells that divide excessively with self-sufficient growth signaling.
• They are insensitive to anti-growth signals.
• Metastasis enables cells to migrate and invade other tissues.
• Angiogenesis is the growth of new blood vessels to supply the tumor.

P53

• A tumor suppressor active at the G1 checkpoint.
• Prevents cells from entering the S phase if there is DNA damage.
• It triggers the production of cell cycle inhibitors and activates DNA repair enzymes.
• Cancer cells often lack functional p53, leading to unchecked cell division.

Telomeres & Telomerase

• Telomeres are DNA "end caps" that prevent gene loss at chromosome ends and appear as damaged DNA, requiring protection from cellular repair systems.
• Telomere shortening is associated with cellular aging.
• Telomerase is an enzyme active in germ and cancer cells that extends telomeres, reversing the aging process in cancer cells.

Chemotherapy

• It uses chemicals to target and kill malignant cells; contemporary approaches harness the immune system.
• Combination therapy employs multiple drugs with different mechanisms and toxicities to target residual cells.
• Dosing involves the largest tolerated doses given repetitively with breaks for the body to recover.
• Chemotherapy targets actively replicating cells in the S and M phases, with cell cycle specificity matched to the cancer type for treatment.

Anesthetic Considerations- Preoperative Evaluation

• Be aware of current chemotherapeutic regimen (expected adverse effects).
• Review CBC, coagulation profiles, ABG, electrolytes, renal & hepatic function.
• Note N/V or diarrhea.
• Know potential effects on anesthetics, other drugs given intraoperatively.
• Review ECG and CXR.

Anesthetic Considerations Preoperative Evaluation

• Note any inflammation of mucous membranes (exercise care with airway devices).
• Determine if chemo-induced peripheral neuropathy is present (assess pain management, regional anesthesia).
• Assess PONV risk.
• Understand the patient's immunosuppression (use aseptic techniques, prophylactic antibiotics).
• The patient is susceptible to iatrogenic infections.

Alkylating Agents

• Non-cell cycle specific, working in all phases.
• Mechanism: Form covalent alkyl bonds with DNA bases, impairing DNA structure and inhibiting replication and transcription.
• Toxic to dividing cells.

Alkylating Agents- Indications

• Hematologic malignancies like leukemia, lymphoma, and multiple myeloma.
• Solid tumors like breast, ovarian, bladder, and lung cancers.

Alkylating Agents- Adverse Effects

• Bone marrow suppression, primarily lymphocytopenia within 24 hours.
• Gonadal dysfunction includes infertility, oligospermia, and amenorrhea.
• GI disturbances include mucosa hypertrophy and shedding.
• CNS stimulants can cause N/V, muscle weakness, and seizures.
• Follicular damage leads to alopecia.
• Pulmonary issues:Pneumonitis, pulmonary fibrosis, and decreased diffusion capacity.
• Cardiotoxicity: Cyclophosphamide can cause pericarditis, pericardial effusion potentially leading to tamponade, and hemorrhagic myocarditis with CHF.
• Hepatotoxicity: Several drugs have boxed warnings.
• Secondary malignancy risk.
• Phlebitis and thrombophlebitis.
• Inhibition of plasma cholinesterase activity occurs for 2-3 weeks post-therapy, increasing the risk of prolonged paralysis with succinylcholine.
• Nephropathy is related to uric acid, possibly requiring allopurinol.
• Acquired resistance is due to decreased cell permeability or increased production of competitive substances.

Platinum Complexes

• Alkylating-like agents are non-cell cycle specific and cause damage in all phases.
• Cisplatin and carboplatin are examples of platinum complexes
• Mechanism: These form crosslinks, disrupting DNA, inhibiting cellular processes and enzymes involved in replication and division.

Cisplatin- Indications

• Solid tumors includng lung, bladder, ovarian, uterine, and testicular cancers.

Cisplatin- Adverse Effects

• Nephrotoxicity (boxed warning): Decreased GFR, increased creatinine, and renal tubular necrosis, leading to ARF.
• Ototoxicity: Tinnitus and hearing loss.
• Peripheral neuropathy (boxed warning): Sensory neuropathies, paresthesias, and loss of vibration and position senses.
• Myelosuppression (bone marrow): Leukopenia and thrombocytopenia.
• Marked nausea and vomiting (boxed warning).
• Hypersensitivity reactions: Facial edema and bronchoconstriction.

Antimetabolites

• Cell cycle-specific, preventing complementary DNA synthesis in the S phase.
• Mechanism: Acts as a false cellular nutrient, mimicking folic acid, enzyme inhibition, and mimicking nucleobases.
• It stops DNA replication and cell proliferation.

Antimetabolites: Indications

• For Hematologic cancers like leukemia, lymphoma, myelodysplastic syndrome.
• Methotrexate can be used for Psoriasis and rheumatoid arthritis.
• Solid tumors include breast, head/neck, osteosarcoma, lung, and mesothelioma.

Antimetabolites- Adverse Effects

• "High Alert" medications.
• Resistance to therapy risks.
• Bone marrow suppression, including leukopenia, thrombocytopenia, and megaloblastic anemia.
• Pulmonary toxicity
• GI toxicity: Ulcerative stomatitis, diarrhea, hemorrhagic enteritis, and intestinal perforation.
• Nephrotoxicity (adequate hydration needed).
• Hepatotoxicity: Cirrhosis risk.
• CNS: Cerebellar syndrome (ataxia), drowsiness, and fatigue.
• Dermatologic toxicity: Dermatitis, increased pigmentation, nail changes, alopecia, and photosensitivity.

Topoisomerase Inhibitors

• Cell cycle specific.
• Mechanism: Inhibition of topoisomerase I or II inhibits the uncoiling of DNA during replication, causing it to overwind and break apart.
• Most active during the S and early G2 phases.
• Anthracycline anti-tumor antibiotics also create free radicals to break DNA strands.

Topoisomerase Inhibitors- Indications

• Solid tumors: lung (esp. small cell), ovarian, testicular, breast, thyroid, bladder, osteogenic, and sarcomas.
• Hematologic: leukemias and lymphomas.

Topoisomerase Inhibitors Adverese Effects

• Cardiotoxicity is associated with doxorubicin and daunorubicin; free radicals disrupt cardiac proteins and cell membranes.
• Dose-related cardiomyopathy can lead to increased serum troponin T and CHF with impaired LV function.
• Fatal cardiomyopathy may occur with bronchitis and progressive ventricular failure.
• Dexrazoxane is a free radical scavenger, protective against damage.

Bleomycin Pulmonary Toxicity Considerations

• Free radical production in the presence of oxygen and iron or copper damages capillary endothelial and alveolar epithelial cells.
• Pulmonary fibrosis may occur.
• Initial signs are dyspnea, hypoxemia, and pneumonitis.
• Pulmonary lesions and infiltrates may develop. Decreased pulmonary diffusion capacity.

Pulmonary Toxicity

• Reports of postoperative respiratory failure in bleomycin-treated patients.
• Minimize crystalloid fluids intraoperatively (consider using a microdrip set) Possible risk in the presence of hyperoxia.
• Recommendation to maintain inhaled O2 concentrations below 30%.
• Short periods of high concentrations may not be harmful.

TI & AntiTumor ABX- Risk Factors

• Preexisting pulmonary damage or renal dysfunction affecting clearance
• Bleomycin within the previous 1-2 months.

T I & AntiTumor ABX Recommendations

• Monitor for Myelosuppression, pancytopenia.
• Monitor for Gl disturbances: N/V and Inflammation with ulcerations.
• Monitor for Alopecia.

Microtubule Inhibitors

• Cell cycle specific with Microtubules active to create cellular architecture and mediate cellular functions (e.g., substance transport, neurotransmission, cell motility).
• Vinca alkaloids bind and inhibit microtubule formation.
• Taxanes bind and inhibit microtubule breakdown.
• Active in Mitosis that ultimately fails to replicate, because the mitosis phase fails & cell dies without replicating..

Microtubule Inhibitors indications

• Vinca alkaloids- Sold tumors: breast and pediatric tumors (e.g., rhabdomyosarcoma, Wilms tumor) & some hematologic issues (leukemias).
• Taxanes (solid tumors): breast, ovarian, lung, and gastroesophageal & some Head/neck and other prostatic issues: prostate and bladder.

Microtubule Inhibitors- Adverse Effects

• Myelosuppression may cause Pancytopena
• Can cause Autonomic neuropathy which may trigger orthostatic HOTN
• May decrease GI motility (paralytic ileus) may result
• Laryngeal nerve paralysis (hoarseness) may occur
• Watch for possible Urinary retention & Dry mouth
• May develop tachycardia.
• Cardiac (Taxanes) may develop: Dysrhythmias & myocardial ischemia
• Possible Edema or effusion.
• Can result in some Neuromuscular issues: Axonal demyelination, motor and sensory Neuropathy
• Observe areflexia, possible sensory nerve Paresthesias and/or Skeletal muscle that may result in: pain, weakness & ataxia.

Microtubule Inhibitors- Neuropathy Anesthetic consideration

• Check the safety evidence for any Neuraxial and/or regional anesthesia as it is very limited.
• Has a risk of with worsening Neuropathy in both regional & general anesthesia.
• Always practice with the lowest effective concentrations for the particular region of local anesthetic.
• Avoid Epinephrine additives
• USe nerve-localization to avoid nerve damage due to injection with a careful and accurate technique (U/S recommended).

Signal Transduction Modifiers

• Cell cycle non-specific that Disrupt growth factor-receptor interactions with interaction of growth factors (normal cells- not cancer) .
• Normal cell division requires growth factors that signal to the receptors for a normal process.

Transduction- Mechanisms

• Mechanism of actions vary across cells: suppression of gonadotropin release by pituitary gland.
• Blocks in estrogen production or estrogen receptors on CA cells
• Antibody treatment may specifically target a over-expressed antigen on CA cells to CA growth factors.
• Antibodies can trigger apoptosis or prevent antigen promotion of growth & replication.

Signal Transduction modifiers- Indications

• Sold tumors: may include: Breast, Ovarian, Prostate, & brain or lung cancer in select instances.
• Auto Immune diseases: Multiples sclerosis,

(Hormone modifiers) Adverse Effects

• Always risk for Thromboembolic events & stroke, that can be linked to increased CVD. This requires a boxed warning on select items.
• Monitor and watch for 2nd or secondary risk with various treatments: especially with tomaxifend
• Possibe Hepatotoxicity that may require Box warning if it results from Flutamide.
• Observe/ monitor for edema increase, and Muscle aches in myalgias as bones weaken over time.

(Hormone modifiers) More Adverse Effects

• Watch for GI disturbances: Anorexia, N/V, Diarrhea.
• Check hormonal changes & report abnormal: Decreased libido, Gynecomastia, or sudden Hot flashes.

Other Targeted Therapies

• Vaccine's: prevent Infections that can lead to CA and prevent liver cancer, and cervical cancer.
• Immunomodulatory drugs may treat Multiple Myelons with antiproliferative actions: Thalidomide ect

Targeted Theories: Cancer immunotherapies

• use Immune checkpoint inhibitors that will Bind to the immune checkpoint protein. These will reprogram cancer cells to attack! This is not ideal, as inflimation issues are treated with immunopressors and even cordsteriods.

Targeted Theories: Adoptive Cellular Therapy

• This is a process with T.Cells: T cells will have altered to become Tumor Cells... There can be a lifer threatening result as cytokines can be realead to cause systemicInflammatory response.