Antineoplastic Therapy: Cancer Principles

• Antineoplastic therapy involves basic cancer principles.

Introduction to Cancer

• Cancer involves uncontrolled growth of abnormal cells.
• Breast cancer is common in women.
• Prostate cancer is common in men.
• Lung and colorectal cancer affect both sexes in high numbers.
• Cancer occurs when the body's control mechanisms stop working.
• Old cells don't die but grow uncontrolled, forming abnormal cells.
• A tumor is an abnormal lump or growth of cells.
• Benign tumors have normal cells and are not cancerous.
• Malignant tumors are cancerous because the cells are abnormal and grow uncontrollably.

Common Characteristics of Cancer Cells

• Malignant tumors exhibit continuous uncontrolled proliferation by being unresponsive to feedback mechanisms.
• Telomerase, active in cancer cells, facilitates repeated cell divisions.
• Dedifferentiation involves a loss of capacity to differentiate and a loss of function
• Invasive growth allows neoplastic cells to penetrate adjacent tissues, facilitating cancer spread.
• Metastasis is the formation of secondary tumors due to malignant cells migrating and re-implanting
• Angiogenesis is the production of growth factors like VEGF to develop new blood vessels for tumor supply.

Benign vs. Malignant Tumors

• Benign tumors are non-cancerous and do not invade surrounding tissues or spread.
• Malignant tumors are cancerous, invade nearby tissue, and can travel to distant areas in the body
• The ability of cancer cells to travel to other sites is called metastasis
• Cancer and malignant tumors are characterized by dedifferentiation, invasiveness, and metastasis, distinguishing them from benign tumors.

Etiology of Cancer

• Cancer is a genetic disease caused by gene changes affecting cell function.
• The genetic changes affect proto-oncogenes, tumor suppressor genes, and DNA repair genes.
• These genetic changes are called "drivers" of cancer.
• Proto-oncogenes are involved in normal cell growth and division but can become cancer-causing genes (oncogenes) if altered.
• Tumor suppressor genes control cell growth and division; alterations can cause uncontrolled cell division.
• DNA repair genes fix damaged DNA; mutations can lead to additional mutations, making cells cancerous.

Phases of the Cell Cycle

• G1 phase: Cell prepares to make DNA.
• S phase: DNA synthesis occurs.
• G2 phase: Cell prepares for mitosis.
• M phase: Mitosis occurs.

Regulation of the Cell Cycle at Internal Checkpoints

• The cell cycle is controlled at three checkpoints.
• The integrity of DNA is assessed at the G1 checkpoint.
• Proper chromosome duplication is assessed at the G2 checkpoint.
• Spindle fiber attachment to each kinetochore is assessed at the M checkpoint.

Regulator Molecules of the Cell Cycle

• Intracellular molecules regulate the cell cycle in addition to checkpoints.
• Regulatory molecules promote cell cycle progression (positive regulation) or halt it (negative regulation).
• Cyclins and cyclin-dependent kinases (CDKs) drive cell cycle progression through checkpoints.
• Cyclins must bind tightly to CDKs, and the Cdk/cyclin complex must be phosphorylated to be active.

Negative Regulation of the Cell Cycle

• Retinoblastoma protein (Rb), p53, and p21 are key negative regulators (tumor-suppressor proteins).
• Rb, p53, and p21 primarily act at the G1 checkpoint.
• p53 is a multi-functional protein.
• Damaged DNA triggers p53 to halt the cell cycle and recruit repair enzymes.
• If DNA damage is irreparable, p53 triggers apoptosis to prevent damaged chromosomes' duplication.
• Elevated p53 levels increase p21 production, inhibiting Cdk/cyclin complexes of activity.
• Elevated p53 and p21 occurs when a cell experiences more stress, reducing the likelihood that the cell will enter the S phase.

Causes of Genetic Alterations

• Chemical carcinogens like tobacco smoke, air pollutants, and water pollutants
• Viruses like Hepatitis C and B (liver cancer)
• Radiation (X-rays)
• Drugs such as estrogen (breast cancer)
• Hereditary factors

Categories of Cancers

• Carcinomas occur in epithelial tissues like skin, lung, stomach, intestines, and blood vessels.
• Sarcomas occur in connective tissues like muscles, bones, and cartilage.
• Leukemias occur in blood cells without forming solid tumors.
• Lymphomas occur in the lymphatic system.
• Brain and spinal cord tumors are named based on cell type and tumor location within the central nervous system.

Stages of Cancer

• Staging describes the location, spread, and affected body parts.
• Diagnostic tests determine the cancer's stage.
• Staging helps doctors to plan treatment, including surgery, chemotherapy, or radiation therapy.
• Staging of cancer helps in predicting the chance of it returning after treatment.
• Staging helps in the doctor predicts the chance of recovery.
• Staging also helps ascertain how the treatment will work.

TNM Cancer Staging System

• T for Tumor indicates the size and location of the primary tumor.
• N for Node indicates if the tumor has spread to the lymph nodes, including the number of affected nodes.
• M for Metastasis indicates if the cancer has spread to other body parts and to what extent.

Cancer Stage Grouping

• The categorization of cancer for each patient is determined via the T, N, M system and further relevant parameters.
• Most cancers include four stages, designated as I–IV, with occasional cancers including stage 0.
• Stage 0: Carcinoma in situ wherein abnormal cells reside within their normal location.
• Stage I: the cancer is localized to one area of the body and is small enough to be surgically removed.
• Stage II and III: Indicate larger cancers that have spread to nearby tissue or lymph nodes.
• Treatment includes chemotherapy, radiation, or surgery.
• Stage IV: Indicates that the cancer has spread to other organs of the body.
• This can be also called advanced or metastatic cancer.
• Treatment includes chemotherapy, radiation, and surgery, but survival rates are significantly lower.
• Generally, the lower the stage, the better the treatment prognosis.

Cancer Grading

• Grading indicates how aggressive the cancer cells are.
• When examined microscopically, the more cancer cells differ from normal ones in appearance, the higher the grade.
• According to the American Joint Committee on Cancer (AJCC):
  • GX: Grade cannot be assessed.
  • G1: Well-differentiated; cancer cells look fairly normal.
  • G2: Moderately differentiated; cancer cells are less normal but still have recognizable structures.
  • G3: Poorly differentiated; cancer cells have a pattern different from normal cells.
  • G4: Undifferentiated; cancer cells are unrecognizable.

Growth Fraction

• Growth fraction represents the ratio of proliferating cells to G0 cells.
• Tissues with a large percentage of proliferating cells and few G0 cells have a high growth fraction, versus tissues with the opposite.
• Antineoplastic drugs are more toxic to tissues with a high growth fraction than to those with a low growth fraction.
• Proliferating cells are especially sensitive to chemotherapy because cytotoxic antineoplastic drugs disrupt DNA synthesis or mitosis.
• Antineoplastic agents' toxicity also extends to normal, rapidly dividing tissues such as bone marrow, GI tract epithelium, hair follicles, and sperm-forming cells.

Cell Cycle Drug Effects

• Drugs that are cell-cycle phase-specific are only toxic to cells within a certain phase of the cell cycle.
• Vincristine causes mitotic arrest and is effective during M-phase while G0 cells will not be harmed.
• These drugs must be present for an extended time to be effective.
• Cell-cycle phase-nonspecific antineoplastic drugs act during any phase of the cell cycle, including G0.
• Alkylating agents and most antitumor antibiotics are in this drug category.
• These drugs are more toxic for proliferating cells than cells in G0.
• Cells in G0 have time to repair drug-induced damage, and their toxicity may not manifest until the cells attempt to proliferate.

Obstacles to Successful Antineoplastic Therapy

• Toxicity to normal cells
• Necessity to produce 100% cell kill to cure cancer
• Absence of truly early detection methods
• Poor response of solid tumors (low growth fraction) to cytotoxic
• Debulking or reduction through surgery or irradiation can improve drug sensitivity.
• Development of drug resistance
• Heterogeneity of tumor cells and limited drug access to some tumors.

Strategies for Achieving Maximum Benefit from Chemotherapy

• Intermittent therapy allows normal cells to recover between treatments.
• Multi-drug chemotherapy (combination therapy) uses multiple drugs together.
• Selecting the right dosing schedule is critical to success.
• Using special techniques for drug delivery increases cell kill while reducing systemic toxicity.

Advantage of Combination Therapy

• Suppresses drug resistance
• Increases cell kill
• Reduces injury to normal cells
• Drugs used in combination therapy should have different mechanisms of action, minimally overlapping toxicities, and good efficacy when used alone.

Resistance

• Mechanisms of drug resistance include a decrease in the amount of drug the cell takes in.
• Results in decreased amount of drugs that accumulate in the cell..
• Insufficient activation and increased inactivation of an administered drug.
• Increased concentration of drug target enzyme and utilization of alternative mechanisms within metabolic pathways.
• The ability of a cell to rapidly repair drug-induced lesions.

Toxicities of Antineoplastic Drugs

• Bone marrow is always affected because chemotherapy affects rapidly dividing cells.
• Myelosuppression can reduce neutrophils, thrombocytes, and erythrocytes, risking infection, bleeding, and anemia.
• Injuring the epithelial lining of the GIT causes stomatitis, diarrhea, nausea, and vomiting (controlled by ondansetron plus dexamethasone).
• Other toxicities include alopecia, fetal malformations, irreversible male sterility, hyperuricemia, renal injury, carcinogenicity, and unique toxicities.