Cell Cycle: G0 and G1 Phases

Cell Cycle Overview

• Cell cycle phases include G0 (resting), G1, S, G2, and M (mitosis).
• Some sources consider five phases.
• Four main cycles relate to DNA and cellular replication/division.
• G1, S, and G2 phases are collectively known as interphase.
• Cells spend 90% of their time in interphase, doubling cytoplasm and synthesizing DNA.
• Human cells typically take 18-24 hours to complete the cycle.

G0 Phase

• Also known as the resting or non-dividing state.
• Cells exit the cell cycle and perform normal functions (e.g., neurons, liver cells).
• Cells can remain in this phase for extended or permanent periods.
• Growth factors and signals can stimulate cells to leave G0 and enter the cell cycle.
• Mutations can cause cells to remain permanently in G0.
• Cancer cells often ignore normal growth signals and exit G0 to replicate unchecked.

G1 Phase

• Cells are recruited into the cell cycle.
• Occurs immediately before DNA synthesis.
• Cells increase in mass and organelles, preparing for division.
• Cells are diploid, containing two sets of chromosomes.

S Phase

• Primarily involves DNA synthesis and chromosome duplication.
• Cells continue to grow.
• DNA checkpoint for error detection; errors trigger repair or apoptosis.
• Absence of errors allows progression to G2 phase.

G2 Phase

• Occurs between DNA replication and meiosis.
• Cells continue to grow and produce necessary molecular building blocks like proteins.
• Additional DNA checkpoint monitors for problems before mitosis.

Mitosis Phase

• The cell divides into two daughter cells with equal content distribution.
• Subdivided into four phases: prophase, metaphase, anaphase, and telophase.
• Prophase: Chromatin condenses into chromosomes and migrates to the cell's center, nuclear envelope breaks down, spindle fibers form.
• Metaphase: Nuclear membrane disappears, spindle develops, and chromosomes align.
• Anaphase: Sister chromatids separate, and spindle fibers elongate.
• Telophase: Chromosomes segregate into new nuclei; cytokinesis begins.
• Cytokinesis: Cytoplasm divides, forming two new cells; starts in anaphase and ends after telophase.

Cancer Development

• Malignant cells have problems with division and DNA synthesis.
• Characterized by rapid replication and abnormal cell cycle regulation.
• Genetic mutations (oncogenes) and problems with regulator proteins occur.
• Cells multiply without necessary growth factors and infiltrate/destroy normal tissue.

Malignant Cell Characteristics

• DNA changes increase cell growth and division.
• Cells escape internal and external division controls.
• Avoid programmed cell death (apoptosis).
• Additional mutations are required for tumor progression.

Tumor Formation

• Tumors are masses of cells dividing excessively.
• Exhibit self-sufficient growth signaling and insensitivity to anti-growth signals like tumor protein p53.
• Metastasis occurs as cells migrate and invade other tissues.
• Angiogenesis develops, where new blood vessels grow.

Role of p53

• Acts as a tumor suppressor, active during the G1 checkpoint.
• Controls the transition to the S phase and responds to DNA damage.
• Triggers cell cycle inhibitors and activates DNA repair enzymes.
• Cancer cells often have missing, nonfunctional, or less active p53.

Telomeres and Telomerase

• Telomeres are DNA "end caps" preventing gene loss at chromosome ends.
• Telomere shortening is related to cellular aging.
• Telomerase is an enzyme that extends telomeres, reversing shortening
• Active in germ cells and some stem cells.
• Cancer cells often activate telomerase, maintaining telomere length.

Chemotherapy Overview

• Broad range of chemicals used to eradicate malignant cells.
• Contemporary therapy aims to harness the power of the intrinsic immune system.
• Combination therapy often includes drugs working via different mechanisms, targeting residual cells and avoiding similar toxicities.
• Largest tolerated doses are administered in repetitive, intermittent regimens.
• Targets cells undergoing active DNA synthesis (S phase) or mitosis.

Chemotherapy - Dosing

• Single doses might not eliminate cancer cells.
• Side effects / toxicities dictate tolerance, necessitating intermittent dosing with breaks.

Anesthetic Considerations

• Preoperative evaluation includes chemotherapeutic regimen, labs (CBC, coagulation, ABG), electrolytes, renal/hepatic function.
• Inflammation of mucous membranes requires caution with airway devices.
• Chemo-induced peripheral neuropathy can impact pain management and regional anesthesia.
• Positive association between chemo-induced nausea/vomiting (CINV) and postoperative nausea/vomiting (PONV) is weak.
• Aseptic techniques and prophylactic antibiotics are critical due to immunosuppression.

Alkylating Agents

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

Alkylating Agents - Indications

• Used for hematologic malignancies (leukemia, lymphoma, multiple myeloma) and solid tumors (breast, ovarian, bladder, lung).

Alkylating Agents - Adverse Effects

• Bone marrow suppression (lymphocytopenia), gonadal dysfunction (infertility), and GI disturbances.
• CNS stimulants contribute to nausea/vomiting, muscle weakness, and seizures.
• Follicular damage (alopecia), pulmonary issues (pneumonitis, fibrosis), and decreased diffusion capacity may also occur.
• Cardiotoxicity (pericarditis, hemorrhagic myocarditis), hepatotoxicity (boxed warning), and secondary malignancy risks are possible.
• May inhibit plasma cholinesterase activity, prolonging paralysis with succinylcholine.
• Nephropathy related to uric acid might require allopurinol.

Platinum Complexes

• "Alkylating-like" agents, non-cell cycle specific.
• Disrupt DNA by crosslinking bases, inhibiting cellular processes.
• Cisplatin and carboplatin are common examples.

Cisplatin Indications

• Treatment of lung, bladder, ovarian, uterine, testicular, and colorectal tumors.

Cisplatin Adverse Effects

• Nephrotoxicity (boxed warning), ototoxicity (tinnitus, hearing loss), and peripheral neuropathy (boxed warning).
• Myelosuppression, marked nausea/vomiting (boxed warning), and hypersensitivity reactions are also possible.

Antimetabolites

• Cell cycle-specific drugs act during the S (DNA synthesis) phase.
• Prevent complementary DNA synthesis by acting as false nutrients and inhibiting enzymes.
• Methotrexate is used for psoriasis and rheumatoid arthritis in addition to cancer treatment.

Antimetabolites indications

• Used for hematologic cancers (leukemia), solid tumors (breast, head/neck, lung, mesothelioma)

Antimetabolites - Adverse Effects

• High-alert medications with risks of resistance to therapy and bone marrow suppression.
• GI toxicity includes ulcerative stomatitis, diarrhea, hemorrhagic enteritis, and intestinal perforation.
• Risk of nephrotoxicity, necessitating adequate hydration, and hepatotoxicity leading to cirrhosis.
• CNS effects include cerebellar syndrome and dermatologic toxicity (photosensitivity, dermatitis).

Topoisomerase Inhibitors and Anti-tumor Antibiotics

• Cell cycle-specific; toposiomerase enzyme corrects alterations during replication and transcription.
• Inhibit uncoiling of DNA during replication, causing DNA to "overwind" and break.
• Anthracycline antibiotics also create free radicals to break DNA strands.

Usage

• Act during the S phase and early G2 phase.

TOPOISOMERASE INHIBITORS - INDICATIONS

• Solid tumors (lung,ovarian, testicular, breast Thyroid, Bladder, Osteogenic, sarcomas
• Hematologic (Leukemias, Lymphomas)

Ti & Anti-Tumor Antibiotics - Adverse Effects

• Cardiotoxicity (Doxorubicin, daunorubicin); create free radicals disrupting cardiac proteins, can cause does-related cardiomyopathy.
• Pulmonary toxicity; Bleomycin creates free radicals in presence of oxygen and iron/copper leading to capillary endothelial and alveolar epithelial damage

Pulmonary toxicity - Anesthetic considerations

• reports of post-operative respiratory failure in Bleomycin treated patients
• Possible risk with Excessive Crystalloid administration, therefore minimize fluids intra-op, consider using microdrip, colloids.
• Possible risk with Hyperoxia, recommendation to maintain inhaled O2 concentrations <30% short periods of high concentrations may not be harmful - Risk factors, renal dysfunction existing pulmonary damage risk for post-operative respiratory failure or using concentrations. Use within previous 1 to 2 months.

Microtubule Inhibitors

• Cell cycle-specific drugs disrupting cellular architecture and functions, act during mitosis.
• Vinca alkaloids and taxanes are two major classes.
• Vinca alkaloids bind and inhibit microtubule formation.
• Taxanes bind and inhibit microtubule breakdown causing mitosis to fail and cell dies without replicating.

Common indications

• Vinca alkaloids, breast pediatric tumors.
• Taxanes, solid tumor lung, gastroesophageal, head/neck.

M I C R O T U B U L E I N H I B I T O R S – A D V E R S E E F F E C T S

• Myelosuppression, Pancytopenia
• Autonomic Neuropathy: Orthostatic Hypotension, decreased Gi mobility paralysis , retention dry mouth, tachycardia ect.
• Cardiac : dysrhythmia. myocardia ischemia, odema
• Neuromuscular: Reflexia , axonal demyelination, motor sensory.

MICRO - Anesthetic consideration for Peripheral Neuropathy.

• Limited Evidence for safety, neuraxial regional limited evidence for. increases of worsening .Use lower concentration of local aesthetic.
• Avoid Epinephrine additive

Signal Transduction Modifiers

• Many variable mechanism of action, non-cell specific.
• Hormones treatments disrupt growth factor receptor interaction.
• Antibody target overexpressed engines cancer cells.
• Antiesterogens, antitumor, antiestrogen monoclonal indicate solid .

Signal Hormones Adverse effects

• Increased Risk for cardiovascular diese, and thromboembolic stroke. boxed warning with secondary malignancy
• Gi disturbances, anorexin, diarrhea etc. Hormonal changes Decreases libido Gynecostria

Other Targeted therapies

• Vaccines
• Immunomodulary drugs (multiple myeloma, anti prolific, anti angiogenic. thalidomine
• Cancer immunotherapies. reprogram immune to attack cancer cells, decrease inflammatory side effects.
• Cell therapies, auto logs genetically attack cells risk for like threating effects. ( systematic inflammatory response ect.)