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The document discusses principles of radiation therapy and chemotherapy in gynecologic cancer. It covers topics such as dose response curves, fractional cell kill, radiation resistance, and cell cycle dependency of cell kill. It also describes basic radiation physics including the four fundamental forces, ionization, excitation, and properties of photons like energy, wavelength, and frequency. Electromagnetic and particulate radiation interactions that can ionize atoms are discussed. Principles of therapeutic radiation production using teletherapy and linear accelerators are summarized.
The document discusses principles of radiation therapy and chemotherapy in gynecologic cancer. It covers topics such as dose response curves, fractional cell kill, radiation resistance, and cell cycle dependency of cell kill. It also describes basic radiation physics including the four fundamental forces, ionization, excitation, and properties of photons like energy, wavelength, and frequency. Electromagnetic and particulate radiation interactions that can ionize atoms are discussed. Principles of therapeutic radiation production using teletherapy and linear accelerators are summarized.
The document discusses principles of radiation therapy and chemotherapy in gynecologic cancer. It covers topics such as dose response curves, fractional cell kill, radiation resistance, and cell cycle dependency of cell kill. It also describes basic radiation physics including the four fundamental forces, ionization, excitation, and properties of photons like energy, wavelength, and frequency. Electromagnetic and particulate radiation interactions that can ionize atoms are discussed. Principles of therapeutic radiation production using teletherapy and linear accelerators are summarized.
Fellow, Philippine Obstetrical and Gynecological Society Fellow, Philippine Society for Cervical Pathology and Colposcopy Diplomate, Society of Gynecologic Oncologists of the Philippines Radiation Therapy Principles Radiation Therapy Principles • The dose response curve of tumor cells after radiation treatment follows a sigmoid curve, no normal tissue damage, only a small proportion of a tumor would be controlled by radiation-induced damage. If one were to treat a total dose that could eradicate almost all the entire tumor, irreparable damage to normal tissue would often occur. • The therapeutic goal of radiation therapy is to balance attempts at maximum local control while minimizing adverse symptoms of treatment and normal tissue damage Radiation Therapy Principles • Fractional cell kill: Each radiation dose kills a constant fraction of the tumor cell population. Tumor cell kill follows a linear quadratic relationship with a potential for cell-mediated repair of radiation-induced damage between dose fractions • Radiation dose rate: Large radiation doses per fraction produce the greatest number of tumor cell kills; these also produces the greater damage burden on normal tissues leading to early and late adverse complications Radiation Therapy Principles • Radiation resistance: Select malignant tumors show reduced radiosensitivity, resulting in slow tumor regression or renewed tumor repopulation during and after radiation treatment. This is associated with (1) enhanced cell-mediated repair of radiation-induced damage, (2) active concentration of chemical radioprotectors, or (3) cellular hypoxia or nutritional deficiency Radiation Therapy Principles • Cell-cycle dependency of cell kill: ▫ Actively proliferating cells are most often killed by radiation therapy ▫ Ionizing radiation imparts its greatest cell-kill effect during the mitotic phase (M phase) and to a lesser extent the late G1 phase and the early DNA synthesis phase (G1/S) ▫ Radiation has little effect during the late synthetic phase (S phase) Cell cycle Basic Radiation Physics • Matter is made up of subatomic particles that are bound together by energy to form atoms • Atom consists of a central core of one ore more positively charged PROTONS and a zero or more uncharged NEUTRONS surrounded by a cloud of negatively charged orbital ELECTRONS Basic Radiation Physics • 4 fundamental forces that hold these subatomic particles ▫ Strong nuclear force: acts over a short range, keeping an atom’s protons from repelling one another because of similar electrostatic charge ▫ Coulomb/ electromagnetic force: binds orbital electrons to the nucleus such that the closer an electron is to the nucleus, the higher the binding energy an electron has. ▫ Weak force ▫ Gravitational force Basic Radiation Physics • When an atom is neutral it has no charge. • When charge is acquired, an atom is said to be ionized • Removal of an orbital electron renders an atom positively charged • Addition of an electron results in a negative charge • Atoms can also undergo excitation, a process whereby an incident particle’s energy is not sufficient to eject an atom’s orbital electron but rather raises one or more electrons to a higher orbital energy state • Though these types of interactions that radiation therapy elicits biologic consequences within tissues Basic Radiation Physics • Radiation itself can be defined as the emission and propagation of energy through space or a physical medium. • Radiation can be particulate, meaning that units of matter with discrete mass and momentum propagate energy (for example, alpha particles, protons, neutrons, electrons) or can be electromagnetic (photons), meaning energy travels in oscillating electric and magnetic fields that have no mass and no charge and that have velocity of the speed of light. • Both particulate radiation and electromagnetic radiation can ionize atoms, events occurring randomly throughout the medium Basic Radiation Physics • In the treatment of gynecologic malignancies, the most common source of radiation is electromagnetic (photon) radiation. • Photons are generally referred to as either x-rays (extranuclear or from the atom) or gamma rays (from the nucleus) based on origin • Important properties of photons include its wavelength (λ). Frequency (v), speed c=(λ v), and energy E=(hv), where h is Planck’s constant Basic Radiation Physics • A photon’s energy E is proportional to its frequency. The higher energies are transmitted at higher frequencies. Frequency of a photon is inversely proportional to the wavelength, electromagnetic radiation with shorter wavelength has higher frequency and thus higher energy. • Energy used is measured in electron volts; 1 eV = 1.6 x 10 -19 J, and it takes approximately 34 eV to generate one ion pair in water Basic Radiation Physics • The photons used to treat gynecologic cancer can be generated either externally at a distance from the patient’s tumor (teletherapy) or internally close to the patient’s tumor (brachytherapy). • Teletherapy x-ray radiotherapy units can deliver a range of photon energies from 50keV to more than 30MeV • Nuclear decay of radioactive isotopes generates the gamma ray photons used in brachytherapy, and such decay or disintegration was measured in curies. One Ci is defined as 3.7 x 1010 disintegrations per second, which is equivalent to the rate of disintegration of 1 g of radium. Modern standard of unit is Becquerel (Bq), which is one disintegration per second or 2.7 x 10-11 Ci Inverse square law
•The transmitted energy
diverges at a distance it travels from the source increases. •This divergence causes a decrease in energy, and the relationship is described by the inverse square law •The inverse square law states that the energy dose of radiation per unit area decreases proportionately to the square of the distance from the site to the source (1/r2) •For example, the dose of radiation 3cm from a point source is only one ninth of the value of the dose at 1cm Therapeutic Radiation Production • Teletherapy in the form of external beam radiation treatment produces ionizing radiation through radioactive decay of unstable radionucleotides such as cobalt (60Co) or more commonly, through acceleration of electrons • Collimators consisting of interleaved bars or custom-made blocks can shape the treatment beam to conform the dose to the target volume • 60Co source has a half-life of 5.263 years and thus the source must be replaced every 5 to 7 years Therapeutic Radiation Production • In the typical linear accelerator unit, electrons are “boiled” off a filament and accelerated under vacuum along an accelerating wave guide using alternating microwave fields • These accelerated electrons can be used to treat the patients themselves or can hit a high Z material transmission target to produce photons of various energies by interaction known as bremsstrahlung or “Braking radiation” • Currently, most treatment machines generate photon energies of 4 to 20 MeV and similar to 60Co teletherapy units have 360-degree gantry rotation around the patient • Typical linear accelerator dose rates are 3 Gy/min at 100cm from the source Therapeutic Radiation Production • Differences between 60Co and linear accelerator: ▫ a 60Co unit is always “on” when the source is not shielded use radioactive decay always occurs, where as a linear accelerator is “on” only when energized because there is no radionucleotide source ▫ The photon spectra are different in that 60Co has a discrete average monoenergenetic energy, whereas linear accelerators produce photons of variable energies and an average energy of one third the maximum generated energy ▫ 60Co produces treatment beams using only gamma ray photons, whereas linear accelerator produces treatment beams of either electrons or x-ray photons depending on its treatment mode 5 Possible electromagnetic (photon) interactions with matter 1. Coherent scattering (<10keV) occurs when an incident photon scatters off an atom’s outer orbital without losing energy. This produces no radiobiologic effect 2. Photoelectric effect (10-60 keV) occurs when an incident photon interacts with an inner orbital electron and the photon’s energy is completely absorbed by that electron. If enough energy is transferred to the orbital electron to exceed the binding energy of the inner orbital electron, it is ejected, leaving a vacancy that an outer orbital electron fills. When the outer orbital electron fills the vacancy, a characteristic x-ray is produced with energy equal the difference in binding energy between the two electron orbitals 3. Compton effect (60 keV to 10 MeV)
•Cells are composed of
biomolecules dissolved in an aqueous solution •Incident photons (p) randomly ionize cellular water to produce an ion radical (water+) and a free fast electron that can damage biomolecules such as DNA •The water ion radical interacts with another molecule of water to form a hydroxyl radical (OH). •Most often formed hydroxyl radicals diffuse throughout the cell, breaking chemical bonds in target tissues such as proteins and DNA 4. Pair production (>10 MeV) occurs when an incident photon has an energy greater than 1.022 MeV. This threshold is required because the photon disappears to form an electron-positron pair. Once formed, free electrons slow by nuclear attraction and are quickly stopped in tissues. Positron emission tomography scanners build images based on coincident detection of photons formed by this process
5. Photodisintegration (>10 MeV): occurs when an energetic
photon penetrates the nucleus of an atom and dislodges a neutron. Emitted neutrons cannot ionize tissue themselves because they have no charge, but rather collide with surrounding atomic nuclei to produce recoil, positively charged protons that elicit radiobiologic effects through subsequent ionizations • One-third of radiation induced DNA damage is from direct interaction of incident photons ionizing atoms within DNA itself • Two-thirds is a consequence of the indirect damage by freely diffusing hydroxyl radicals (.OH) • As the time interval between radiation doses lengthens, cell survival increases due to the prompt repair of radiation-induced damage. The repair process is usually complete within 1 to 2 hours, although may be longer in some slowly renewing tissues Radiation biology • Intracellular molecular oxygen importantly modifies radiation-induced DNA damage as it “fixes” damage by free hydroxyl radicals. Molecular oxygen, when present, reacts with the altered chemical bonds of ionized molecules to produce organic peroxides, the nonreparable form of the target molecule. Molecules “fixed” in this manner are permanently altered and may function abnormally. • Practical implications in radiation therapy in gynecologic cancers: rapidly proliferating malignancies, may have poor blood supply, which decreases tumor cell oxygenation, particularly at the center. Tumor tissue hypoxia leads to radiation resistance Radiation biology • The radiation dose necessary to kill the same proportion of hypoxic cells as compared to aerated approaches 3:1. This ratio is commonly referred to as the oxygen enhancement ratio. For oxygen to have its maximal effect, dissolved oxygen concentration in tumor must be approximately 3mmHg (venous blood is 30-40mmHg) • In cervical cancer, serum hemoglobin greater than 10md/dL have improved tumor oxygenation Radiation biology • LET-rate of energy lost per unit length of medium, imparts an effect on the accumulation of radiation induced DNA changes. • Low LET radiations produce one or more sublethal events and thus necessitate multiple “hits” to kill the cell • Heavy particulate radiation resulting from alpha particles or photons is densely ionizing as energy is deposited more diffusely along its path, typical of high LET radiation. High LET radiation- producing high probability of lethal event in the cell. Cell death is independent of tumor oxygenation Cell Survival curves •Cell death following radiation therapy is modeled by a linear quadratic relationship •The initial slope of the cell survival curve is shallow and curvilinear, whereas the terminal slope is more linear •In the low dose region of the survival curve typical of daily-dose fractions used in radiation therapy, the fraction of cells surviving is high due to the repair of single- event sublethal damage •In the high dose region of the survival curve, the fraction of cell surviving in the form of DNA double-stranded breaks or accumulation of too many sublethal events that can be repaired before the next cell division Phases of the cell •After mitosis (M), there is an interval of variable duration during which there is RNA and protein synthesis and a diploid DNA content (G1) •The cell may also enter a prolonged or resting phase (G0) and then reenter the cycle during DNA synthesis, the S phase, in which DNA is duplicated. •During the G2 phase, there again is protein and RNA synthesis. •During the M phase, the cell divides into two cells, each of which receives diploid DNA Brachytherapy • Involves the placement of radioactive sources within an existing body cavity, eg., the vagina • Radioactive sources are “afterloaded” some time later to reduce radiation exposure to medical personnel • The most widely used intracavitary applicator is the Fletcher-Suit applicator, which is useful for treatment of a cervical tumor or a tumor located near the cervix • Radioisotopes with a short half-life such as 198Au may be placed within the patient and left permanently. Those with long half-life 137Cs are placed temporarily and are removed after prescribed dose of radiation Brachytherapy Half-Lives of Commonly Used Radioisotopes for Gynecologic Malignancies Radionuclide Half-life Gold (198Au) 2.7 days Phosphorus (32P) 14.3 days Iridium (192Ir) 73.8 days Cobalt (60Co) 5.26 years Cesium (137Cs) 30 years Radium (226Ra) 1620 years Teletherapy • In the form of external beam radiotherapy means that the source of radiation is at a distance from the patient, sometimes located at a distance 5 to 10 times greater than the depth of the tumor being irradiated. This distance is referred to as SSD (source to surface distance) • Collimators limit scatter radiation and block portions of the treatment beam from delivering intolerant radiation dose to critical tissues Teletherapy •Isodose curves and depth dose distributions for 6 and 22 MeV photons shown •For the 6 MeV, the maximum dose near the surface with a more rapid falloff in the deeper tissues •For the 22MeV, the maximum dose is deep to surface, sparing the effects of radiation on the underlying skin Tissue Tolerance and Radiation Complications • Early or acute effects: which involves tissues undergoing rapid cell division to replace lost normal functioning cells. Eg., skin, intestinal mucosa, mucosa of the vagina and bladder, and the hematopoietic system • Late effects occur after a delay of months or years after radiation therapy. Late effects often a product of parenchymal connective tissue cell loss and vascular damage. Late effects may be seen in slowly renewing tissues such as lung, kidney, heart, liver and CNS • Late adverse effects include necrosis, fibrosis, fistula formation, ulceration Tissue Tolerance and Radiation Complications • Erythema progressing to dry or moist skin: treat with non- metal containing creams and emollients • Late skin fibrosis: use pentoxifylline and vitamin E • Radiation cystitis manifested as dysuria, frequency treat with analgesics such as pyridium • Hematuria: use sclerosing solutions or fulguration through a cystoscope • Damage to bowel (sigmoiditis/enteritis)manifesting as increased bowel motility or diarrhea: low roughage diet and antispasmodic; worst cases bowel resection/colostomy • Hematologic: growth factors: erythropoietin, granulocyte colony stimulating factor • Fistulas: diverting surgery or resection of fistula Normal Tissue Tolerance to Radiation Tissue Tolerance (Gy) Kidney 20-23 Gy Liver 25-35 Gy Small Bowel 45-50 Gy Rectum 60-70 Gy Bladder 60-70 Gy Vaginal mucosa 70-75 Gy Cervix >120 Gy Chemotherapy Principles and Guidelines • Fractional cell kill: Each dose of chemotherapy kills a constant fraction of the tumor cell population. Tumor cell kill correlates usually in a linear relationship with the pharmacokinetic parameter of the area under the drug concentration curve (AUC) • Dose intensity: High chemotherapy doses interspersed with short test periods produce greatest tumor cell kill in rapidly proliferating malignancies Chemotherapy Principles and Guidelines • Drug resistance: Single-agent chemotherapy administration selectively isolates drug-resistant tumor cells, leading to an outgrowth of hardy, resistant malignant cells. Chemotherapy drug resistance has been associated with (1) cell- mediated modification of drug agents, (2) active drug transport out of the cell and, (3) alteration of drug activation or targeting • Cell cycle dependency of cell kill Approaches to treatment • Dose of anticancer chemotherapy agent is usually calculated as a function of body surface area (square meters) • Bone marrow toxicity- measure ANC-absolute neutrophil count, platelet counts, use growth factor, dosage reduction • Hepatic metabolism and/or renal excretion, eg doxorubicin and vincristine-metabolized in the liver Approaches to treatment • Methotrexate and cisplatin- effects increased with those with renal damage; both bound to albumin and this binding is decreased if patient taking sulfonamides or salicylates • Chemotherapy can cause loss of ovarian function and fertility 4 ways in which chemotherapy is generally used 1. As an induction treatment for advanced disease (neoadjuvant therapy) in which additional treatment following chemotherapy is planned 2. As an adjunct to radiation therapy 3. As primary treatment for cancer 4. By instillation into specific regions of the body (e.g., intraperitoneal chemotherapy RECIST (Response Evaluation Criteria in Solid Tumors) Criteria to Assess Clinical response to Therapy • CR (Complete response) –disappearance of all target lesions • PR (Partial response)- 30% decrease in the sum of the greatest diameters of target lesions • PD (Progressive Disease)- 20% increase in the sum of the greatest diameters of the target lesions • SD (Stable Disease)- small changes that do not meet the above criteria Evaluation of New Agents • Phase I Trial: tests new drugs at various doses to evaluate toxicity and to determine tolerance to the drug. At the various doses tested, some therapeutic effects may be observed, although this is not the primary aim of the trial • Phase II Trial: Tests the therapeutic effectiveness and extent of toxicity of the drug at doses expected to be effective against a specific tumor type • Phase III Trial: Compares new treatment therapies against treatment currently in use. For instance, this trial design assess whether a new drug therapy is superior, equivalent, or inferior to the chemotherapy currently in use Assessment of Performance Status Score Karnofsky Performance Status 100 Normal, no complaints; no evidence of disease 90 Able to carry on normal activity; minor signs or symptoms of disease 80 Normal activity with effort; some signs or symptoms of disease 70 Cares for self but unable to carry on normal activity or do active work 60 Requires occasional assistance but is able to care for most personal needs 50 Requires considerable assistance and frequent medical care 40 Disabled; requires special care and assistance 30 Severely disabled; hospitalization indicated, although death not imminent 20 Very sick; hospitalization necessary’ active support treatment necessary 10 Moribund; fatal process progressing rapidly 0 Dead Assessment of Performance Status Grade Gynecologic Oncology Group Performance Status Scale 0 Fully active, able to carry on all predisease performance without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work 2 Ambulatory and capable of all self-care but unable to carry out any work activities; Up and approximately ≥50% 0f waking hours 3 Capable of only limited self-care, confined to bed or chair >50% of waking hours 4 Completely disabled; cannot carry on any self-care; totally confined to bed or chair 5 Dead Chemotherapy cell-cycle activity •Alkylating agents facilitate transfer of alkyl groups to DNA, disrupting the G1/S transition •Agents derived from bacteria deregulate normal DNA and RNA processing, slowing progression through the G1/S and G2/M transitions •Antimetabolites result in faulty base insertion into replicated DNA or specifically inhibit rate-limiting enzymes such as a ribonuclease reductase that are needed to produce deoxyribonucleotides for DNA replication during the S phase •Taxanes and vinca alkaloid agents alter the mitotic spindle during mitosis, preventing cell division •Platinum agents show activity throughout the cell cycle and cycle form DNA structural adducts limiting progression at various cell cycle checkpoints Platinum Agents • Cisplatin and Carboplatin • Primary treatment for ovarian, tubal, peritoneal, endometrial, cervical, and vulvar cancers as well as GTD • Cisplatin binds to DNA causing intrastrand, interstand and protein adducts and thereby interferes with DNA processing and replication synthesis • Cisplatin is nephrotoxic, copious administration and mannitol infusion prevent renal tubular necrosis Platinum Agents • Cisplatin induces myelosuppresion, high frequency ototoxicity, severe peripheral neuropathy, hypomagnesemia, hypokalemia, seizures, nausea and vomiting • Carboplatin is an analogue of cisplatin. Its mechanism of action and antitumor activity is similar to cisplatin. It is relatively nontoxic to the kidney but more prone to leukopenia, thrombocytopenia and anemia . Dose is usually based on AUC, Typical dose 5-7 computed as dose in (mg) = AUC x (creatinine clearance + 25) Taxanes • Paclitaxel (Taxol) and its synthetic analogue docetaxel (taxotere) are derived from the bark of the Western yew tree (Taxus baccata) • Both promote microtubule assembly and inhibit depolymerization of tubulin during mitosis. By arresting cell division through a functional block of the M phase • Side effects: hypersensitivity reactions, hypotension, neutropenia (major toxic effect), sensory peripheral neuropathy • Used in the treatment of ovarian, cervical, endometrial cancers and uterine sarcomas Antitumor Antibiotics • Actinomycin D (Dactinomycin) • Doxorubicin (Adriamycin) • Bleomycin (Blenoxane) Actinomycin D • Derived from the bacteria Streptomyces parvulus and used primarily for the treatment of GTD • Drug lodges between adjacent purine-pyrimidine (guanine-cytosine) base pairs blocking DNA- dependent ribosomal RNA synthesis by RNA polymerase • Maximally effective in the G1 phase, but data suggest that the drug may act all throughout the cell cycle • Causes myelosuppression- leukopenia and thrombocytopenia , emesis, stomatitis, non-bloody diarrhea, reversible alopecia, skin erythema Doxorubicin • Doxorubicin (Adriamycin) and its newer liposomal formulation (Doxil) are anthracyclines derived from the bacteria Streptomyces peucetius var. caesius. • Drug wedges between stacked nucleotide pairs in the DNA helix and because of its bulk, inhibits the enzymes needed for DNA-directed RNA and DNA transcription as well as DNA replication • Maximal activity in the G1 and S pases, second mechanism includes inhibition of topoisomerase II in the G2 phase. Topoisomerase assists in the coiling and supercoiling of DNA prior to mitosis Doxorubicin • Must be careful not to cause extravasation during administration because it can lead to soft tissue and skin necrosis and ulceration • Causes myelosuppression, complete but reversible alopecia, binds with cardiac myocytes leading to congestive heart failure • Adriamycin encapsulated with liposomes (Doxil), less cardiotoxic Bleomycin • Derived from bacteria Streptomyces verticillis • When complexed with ferrous iron, is a potent oxidase producing single-stranded DNA breaks by hydroxyl radical formation • Toxic to the lungs, pnemonitis and pulmonary fibrosis • Effective against ovarian germ cell tumors Antimetabolites • Interfere with cell metabolism by competing with naturally occurring purinse and pyrimidines • 5-Fluorouracil(5-FU) • Methotrexate • Gemcitabine 5-FU • Is a fluorinated pyrimidine analogue resembling the DNA nucleoside thymine and different from the RNA nucleoside uracil by a fluorinated carbon in the fifth position in the nucleoside ring • Conversion of 5-FU into a fluorodeoxyuridine monophosphate blocks DNA synthesis by covalently binding to thymidylate synthase. This inhibits the formation of de novo thymidylate, a necessary precursor of thymidine triphosphate that is essential for DNA synthesis and cell division • 5-FU perturbs normal progression through the G1/S transition 5-FU • One advantage is that 5-FU can be administered as a bolus or continuous infusion or orally as a prodrug that is metabolized to 5-FU (capecitabine-Xeloda) • Stomatitis, diarrhea, alopecia, nail changes, dermatitis, acute cerebellar syndrome, cardiac toxicity, hyperpigmentation over the vein used for infusion, and hand=foot syndrome • Used in conjunction with cisplatin as a radiosensitizer in the treatment of advanced cervical and vulvar cancer Methotrexate • A folic acid analogue that binds tightly to dihydrofolate reductase, which plays a critical role in intra cellular folate metabolism. This prevents metabolic transfer of one carbon unit within the cell and thereby arrests DNA, RNA, and protein synthesis • Predominant sensitivity to the S phase of the cell cycle • Administered IM, IV or orally • Severe myelosuppression, stomatitis, nausea, emesis, hepatotoxicity • Used in GTD Gemcitabine • A synthetic deoxycytidine nucleoside analogue, targets ribonucleotide reductase (RR), the rate limiting enzyme in the deoxyribonucleotide metabolism during the S phase. RR enzyme used to transform ribonucleotides into deoxyribonucleotides needed for DNA replication • Toxicities: myelosuppression, elevation of liver enzymes, nausea, vomiting, flu-like symptoms, and fatigue. • Used in the treatment of recurrent ovarian carcinoma and uterine sarcoma Alkylating agents • Facilitates the replacement of hydrogen for an alkyl group, potentially disrupting normal function of the altered molecule. They interact directly with DNA by transferring positively charged alkyl group to negatively charged chemical groups intrinsic to the DNA molecule. • Examples of this class: Cyclophosphamide and Ifosfamide • Side effect: severe myelosuppression Alkylating agents • Cyclophosphamide and its structural analogue ifosfamide are bifunctional cyclic phosphamide esters of nitrogen mustard • Both interacts with the N7 position of guanine within the DNA helix to form cross-link bridges between the same strand of DNA (intrastrand), opposite strands of DNA (interstrand), and between DNA and cellular proteins • Disrupts G1/S phase • Inactivated by liver and excreted by the kidney Alkylating agents • Urinary metabolite ACROLEIN results in hemorrhagic cystitis • Prophylactic hydration and administration of 2- mercaptoethane sulfonate (MESNA), a compound that binds acrolein, prevents urotoxicity • Leukopenia, thrombocytopenia. Alopecia, nausea and emesis and amenorrhea Vinca (Plant) Alkaloids • Vinblastine • Vincristine • VP-16 (Etoposide) • Vinblastine and vincristine are derived from the periwinkle plant (Vinca rosea), both block the assembly of tubulin and causing toxic destruction of the mitotic spindle, which arrests cellular mitosis • Vinorelbine is a synthetic vinca alkaloid derived from vinblastine and is a radiosensitizing agent Vinca (Plant) Alkaloids • VP-16 (Etoposide) is a epipodophyllotoxin derived from the root oft he May apple or mandrake plant, stabilizes DNA strand breaks made by topoisomerase II during coiling and supercoling of DNA during mitosis • Affects late G1 and M phases • Vincristine is neurotoxic- numbness, motor weakness and constipation • Vinblastine is myelotoxic, but tend to be dose limiting • VP-16 is myelotoxic, induces anorexia, nausea, emesis, stomatitis, severe hypotension • Uncommon toxicities: cardiotoxicity, bronchospasm and somnolence • Drugs are used to treat ovarian germ cell tumors, cervical cancer (vinoreline), and GTD Topoisomerase inhibitors • Topoisomerases are DNA enzymes that control the topology of DNA double-helix cellular functions during transcription and replication of genetic material • Topotecan, a topoisomerase I inhibitor, is used in the treatment of cervical cancer and epithelial ovarian tumor • Topotecan is a semisynthetic analogue of camptothecin, a chemical derived from the Camptotheca accuminata tree native to China • Greatest activity during G1/S • Toxicities: bone marrow suppression, nausea, vomiting, alopecia, mucositis and diarrhea Growth Factor receptors Targeting and Hormone Therapy • EGF family transmembrane receptor kinases: HER2, HER3, HER4 and EGFR • HER2 and EGFR overexpression results in relative radioresistance among cancer, and therefore drugs that target these receptors may promote radiosensitization • The chimeric antibodies against EGFR (Cetuximab, Erbitux) and HER2 (trastuzumab, Herceptin) are being investigated in gynecologic cancers Growth Factor receptors Targeting and Hormone Therapy • VEGF(vascular endothelial growth factor)- receptor- targeted therapies have emerged as clinically efficacious antiangiogenic and tumor-vasculature-stabilizing agents • Bevacizumab (Avastin)- inhibit new blood vessel proliferation limit successful growth of malignant cells • VEGF render small vessels hyperpermeable to circulating macromolecules, promoting steady tumor cell oxygenation (and thereby enhancing radiation sensitivity) and limiting intermittent tumor hypoxia from random opening and closing of small vessels • Used in advanced ovarian cancer Growth Factor receptors Targeting and Hormone Therapy • Hormone therapy has been effective in the treatment of breast cancer • Estrogen and progesterone receptors clearly identified in endometrial cancer and ovarian epithelial carcinoma • Progestins such as megestrol (Megace), depo- medroxyprogesterone (Depo-Provera), and 17-OH progesterone caproate (Delalutin) as well as antiestrogens as tamoxifen and raloxifene, have been used in the treatment of endometrial carcinomas and seem to have their best effects against well-differentiated tumors Good morning!