PHARM 126: Anticancer Medications and Neoplasms

• Anticancer medications are the subject of PHARM 126: Pharmacology for Pharmacy 2, taught by Lect. Jarvin Enosh T. Tan and Asst. Prof. Jean Flor C. Casauay

Cancer

• Cancer is a neoplastic disease where abnormal cells divide uncontrollably, invading other tissues due to DNA mutations
• Neoplasm is an equivalent term for cancer
• Related terms include cyst and tumor

Cyst vs Tumor

• A cyst is an abnormal sac or closed cavity filled with liquid or semisolid matter and is similar to pus
• A tumor is a mass observed as a lump in the body

Tumor Palpation

• A tumor is rock-hard and non-movable when palpated

Inflammatory Breast Cancer

• Inflammatory breast cancer lacks a distinct lump and is still classified as cancer
• The skin on the breast appears red, warm, and the affected breast may enlarge, firm, tender, or itchy
• Inflammatory breast cancer can grow as large as 16.5 kg
• Enlargement is due to inflammation, resulting in a firmer and less palpable texture
• Inflammatory breast cancer is aggressive

Signs and Symptoms of Inflammatory Breast Cancer

• Sudden and visible breast enlargement, discoloration of the skin, an inward turning of nipple, and tenderness and pain in the affected area are some signs of inflammatory breast cancer
• Skin discoloration ranges from reddish to purplish

Inverted Nipple

• Normal if both breasts have inverted nipples, usually in young adults
• Abnormal if there is a sudden change or protrusion to an inward nipple

Benign vs Malignant Tumors

• Benign tumors are harmless and do not invade surrounding tissues
• Malignant tumors are cancerous, invade and metastasize to all parts of the body, and can be fatal

Metastasis

• Malignant tumors metastasize without control unless intervention is applied

Metastasis of Cancer Cells

• Cancer cells can easily leak out (leakage), affecting other body parts, it's a general term, not only for cancer cells
• Breast cancer cells that have metastasized in the lungs are still considered breast cancer cells and are not to be called lung cancer itself

Angiogenesis

• The growth of new blood vessels from preexisting vessels
• Cancer cells divide quickly, requiring more nutrients, increasing the need for additional blood vessels for cancer cells to grow their own blood supply

Established Cancer Treatments

• Surgery, radiation therapy, chemotherapy, hormone therapy, and stem cell transplant are all established cancer treatments

Surgery Examples

• Hysterectomy, removal of a portion or all of female reproductive system
• Ovaries
• Mastectomy, removal of breast(s)
• Vasectomy

Chemotherapy

• Chemotherapy focuses on using cytotoxic and other drugs, will kill cells, especially targeted to cancer cells

Goals of Chemotherapy

• Chemotherapy aims to provide palliation, cure, act as an adjuvant, or as neoadjuvant

Palliation

• Palliation alleviates symptoms and prolongs life, improving the quality of life by alleviating signs and symptoms

Cure

• Cure aims for eradication

Adjuvant Chemotherapy

• Given after initial treatment such as surgery and/or radiotherapy
• The ideal goal is to cure all cancer types, however reality shows only certain stages are curable

Neoadjuvant Chemotherapy

• Starts with chemotherapy followed by surgery and/or radiotherapy

Drug Combination

• Drug Combination leads to ↑ efficacy, but it also leads to ↑ toxicity

Side Effects of Treatments

• Affects all rapidly proliferating cells which include hair cells or follicles and cells in the gastrointestinal tract, resulting in hair loss

Overview of the Cell Dvcles

• Cell cycle is divided into Cell-cycle Specific and Cell-cycle Non-Specific

Cell Cycle-Non Specific

• Effective against cancer cells regardless of active division, even dormant cells

Cell cycle-Specific

• Anti-cancer drugs work in cancer cells that are actively dividing and are phase-specific or phase non-specific

Cell Cycle Phases

• Interphase includes G1, S, and G2 phases
• Mitotic phase

Interphase

• S = Synthesis, G = Gap

Phases

• In G1 Phase, organelles are duplicated during cell division
• In G0 phase, some cells become dormant (non-diving) and exit the active cell cycle
• In the S phase, DNA replication takes place
• In the G2 phase, duplicated DNA is rechecked

Cell Cycle Specific Agents

• Anti-cancer drugs
• Note: the "active cell cycle" does not include GO

Phase-Specific Agents

• Most active against cells in a specific phase of the active cell cycle which include
• M-phase by vinca alkaloids
• G1 phase by asparaginase or prednisone
• S phase b antimetabolites
• G2 phase by bleomycin or etoposide

Phase-Non-Specific Agents.

• Effective while cells are in the active cycle but cell does not need to be ina particular phase, this includes:
• Alkylating agents
• Antitumor antibiotics
• Cisplatin

Cell Cycle Non-Specific Agents

• Effective in all phases including G0
• Ex: Nitrosoureas and Radiation

Anti Cancer Drags

• Plant Alkaloids
• Antibiotic Anticancer Agents
• Hormonal Agents
• Alkylating Agents
• Antimetabolites
• Miscellaneous Anticancer Drugs

Plant Alkaloids

• Sourced from Vinca rosea (Catharanthus roseus), Periwinkle plant, and Chichirica plant

Plant Alkaloid Agents

• Vincristine
• Vinblastine
• Vindesine
• Vinorelbine

Plant Alkaloid MOA

• Specific to the M (mitotic) phase
• Binds to microtubules, the formation of drug-tubulin complex
• The complex terminates the formation of microtubules by promoting depolymerization (disassembly) and preventing the "rescue” of microtubules

Plant Alkaloid MOA Continued

• Disrupts formation of the mitotic spindle blocking chromosomal migration, and cell division.
• Microtubules are only stable if they end with a GTP-tubulin cap
• With no microtubules, there will be no mitotic spindle and no cell division (mitosis)
• Promotes GTP hydrolysis, preventing the GTPtubulin cap and depolymerizing the microtubule
• Prevents microtubule assembly

Plant Alkaloid Indications

• Vinblastine for Testicular Cancer
• Vincristine for Hodgkin's Lymphoma and Wilms Tumor

Plant Alkaloid ADRS

• Vinblastine result in Nausea and Vomiting, Alopecia, Bone marrow Suppression
• Vincristine result in Neurotoxicity and Peripheral Neuropathy

Taxanes

• Derived from Western yew (Taxus brevifolia) and European yew (Taxus baccata)

Taxanes Agents

• Docetaxel (Taxotere®)
• Paclitaxel (Taxol®)
• Cabazitaxel

Taxanes MOA

• M-phase, late G2 phase specific
• Binds to and stabilize microtubules by enhancing tubulin polymerization
• Block dynamic instability by stabilizing GDP-bound tubulin in the microtubules, forming weak polymers, clogging microtubules inhibiting cancer cell division, eventually leading to apoptosis
• Microtubules that are unable to depolymerize, the cell becomes stuck at metaphase and cannot continue dividing
• Taxanes prevent microtubules assembly and disassembly

PODOphyllotoxins

• Extracted from the root mayapple (Podophyllum peltatum)

PODOphyllotoxins

• Etoposide
• Teniposide

PODOphyllotoxins MOA

• Inhibits topoisomerase II
• Causes the double strand DNA to break
• The function of topoisomerase (green circle) during DNA replication is to unbind the tangle in DNA strands

ADRS

• Etoposide treat Monocytic leukemia, Testicular cancer, and Lung carcinoma
• Teniposide treat Lymphomas

Camptothecins

• Camptotheca acuminata

Camptothecins Agents

• Topotecan
• Irinotecan

Camptothecins MOA

• Inhibit topoisomerase I
• Cause single strand DNA breaks
• Irinotecan is metabolized to active topoisomerase I inhibitor, SN-38 (active metabolite of irinotecan)

Camptothecins Indication

• Topotecan treat Metastatic ovarian cancer
• Cisplatin-resistant neoplasm
• Irinotecan treat Colon rectal cancer

Camptothecins ADRS

• Topotecan induce Neutropenia, Thrombocytopenia Anemia, Alopecia, Myelosuppression, Nausea and vomiting,
• Irinotecan cause early diarrhea, delayed/late Diarrhea, and Myelosuppression and Nausea and vomiting

Antibiotic Anticancer Agents

• Isolated form from Streptomyces peucetius varcaesius and acts on S phase

Antibiotic Anticancer Agents Agents

• Daunorubicin
• Doxorubicin
• Idarubicin
• Epirubicin

Antibiotic Anticancer Agents MOA

• Stabilizes topoisomerase II after it cuts and unwinds DNA strands for replication, preventing topoisomerase from reattaching to broken ends of DNA
• Process by which drug slides between DNA base pairs and inhibits DNA

Stabilizes topoisomerase II Indication

• Doxorubicin treats breast, ovarian, thyroid, lung cancers and acute leukemia
• Daunorubicin & Idarubicin treats Acute leukemia

Antibiotic Anticancer Agents ADRS

• Cardiotoxicity is its main limitation
• Total alopecia and Bone marrow suppression

DACTINOMYCIN

• Binds between adjacent guanine-cytosine base pairs
• Inhibits RNA synthesis by blocking DNA-dependentRNA polymerase
• Used often in pediatric cancers, such as Wilm's tumor (kidney CA)
• Bone marrow depression
• Nausea and vomiting Causes "radiation recall"

Bleomycin

• From Streptomyces verticillus
• Causes DNA strand breaks due to oxidation of DNA-bleomycin-Fe(II) complex, producing toxic free radicals, inhibiting DNA synthesis

Hormonal Agents

SERMS Agents

• Tamoxifen
• Toremifene
• Raloxifene

SERMS MOA

• Have antiestrogen activity in the breast
• Tamoxifen & Toremifene treats hormone receptor-positive breast cancer
• Tamoxifen & Raloxifene reduce risk for women at high risk of breast cancer
• Raloxifene treats osteoporosis

SERMS ADRS

• Hot flashes
• QT prolongation (Toremifene)

SERMS Interactions

• Tamoxifen has estrogenic activity in the endometrium and can increase the risk for endometrial cancer

SERMS Precaution

• These agents also carry the risk for thromboembolic events

Estrogen Receptor Antagonist

• Fulvestrant

Estrogen Receptor Antagonist MOA

• Competitively binds to the estrogen receptor on tumors
• Blocks the action of estrogen to inhibit tumor growth

Estrogen Receptor Antagonist Indication

• Fulvestrant treats Hormone-positive breast cancer

Aromatase Inhibitor Agents

• Aminoglutethimide
• Anastrazole Note: This is not the same as the hormone
• Letrozole

Aromatase Inhibitor MOA

• Overall: inhibits estrogen formation

Aromatization

• *Aromatisation – conversion of androgen to estrogen. The reverse process, conversion of estrogen and androgen naturally, is impossible to occur
• *see Annex 1 for better resolution
• *Inhibitor of adrenal steroid synthesis at the first stem, which is conversion of cholesterol to pregnenolone
• Inhibits extra-adrenal synthesis of sterone and estradiol

Aromatization Indication

• Aminoglutethimide, Anastrazole, and Letrozole treats Breast cancer in postmenopausal women

Gonadotropin-Releasing

• Agents responsible for follicle-stimulating hormone and luteinizing hormone from their anterior pituitary gland

Gonadotropin-Releasing Hormone (GNRH)

• Synthesized and released from the hypothalamus
• Responsible for release of FSH and LH from anterior pituitary gland
  • FSH: regulates development, growth, pubertal maturation and reproductive processes of the body
  • LH: triggers the production of testosterone and estrogen

Gonadotropin-Releasing Hormone (GNRH) Agents

• Leuprolide
• Goserelin

Gonadotropin-Releasing Hormone (GNRH) MOA

• Initially stimulate release of FSH and LH
• Inhibit release of those hormones, reducing testicular androgen synthesis
• Inhibit gonadotropin secretion
• Long term adminstration results in suppression of LH and testosterone dihydrotestosterone

Gonadotropin-Releasing Hormone (GNRH) Indication

• Advanced prostate cancer
• Advanced breast cancer (Goserelin)

Gonadotropin-Releasing Hormone (GNRH) Agent ADRS

• Hot flashes
• Gynecomastia
• Low Sexual desire
• Decrease bone mineral density

Gonadotropin-Releasing Hormone (GNRH) Agent Precaution

• Initial administration may flare the tumor
• Tumor flare of is administered with antiandrogens

Androgen synthesis inhibitors

Androgen 1 synthesis inhibitors agents

• Abiraterone and Ketoconazole

MOA of Androgen synthesis inhibitors agents

• Inhibits CYP17 to inhibit formation of testosterone precursor
• Aromatization Indication

Indications of Androgen synthesis inhibitors

• metastatic castration-resistance prostate cancer

ADRS of Androgen synthesis inhibitors

• Abiraterone for edema and faitgue

Intercation with Androgen synthesis inhibitors

• Abiraterone: edema and fatigue
• Ketoconazole: N&V, skin rash

Antiandrogens agents-first generation

• Flutamide
• Bicalutamide
• Nilutamide

M.O.A of first generation Antiandrogens agents

• blocks testosterone affects at the androgen receptor prevents stimulation of cell growth in prostate agent.

Indication for first generation Antiandrogens agents

• advances prostate cancer in combination with GnRH or signical castration .

###ADRS for first generation of Antiandrogens agents

• Loss of libido
• Impotence
• *Flutamide: Hepatic failure_
• *Nilutamide: Interstitial pneumonitis

M.O.A for second generation

• Pure androgen receptor signaling inhibitor which leads cellular opoptosis and decreases prostate hormone, it acts more quickly.

Alkylating agents

• Cause of cellular apoptosis but decrease prostate tumor volume

Agents of Alkylating agents

• Nitrogen Mustards
• Nitrosoureas
• Alkylsulfonate
• Platinum Analogs

M.O.A Agents of Alkylating agents

• Nitrogen Mustards
• Nitrogen Mustard is a nitrogene base analog of mustard

Alkylating agent Indications

• treat Hodgkin's and non-Hodgkin's lymphoma

Mechlorethamine

• A nitrogen-based analog of mustard gas
• A cytotoxic and vesicant agent

M.O.A Mechlorethamine

• Work in all phases of the cell cycle
• Cause cross-linking & abnormal base pairing of DNA strands that inhibit replication of the DNA
• Alkylation = cross-linking of DNA strands; deviating from A-T and G-C normal base pairing

M.O.A of Alkylating agents

• Involve intramolecularCyclizatiion and reactions with a basse such as N7 of quanine in Dna producing a alkylate purine

Anti-Metabolites Agents

• Folic acid analog

MoA of Anti-Metabolites Agents

• Irreversibly inhibits dihydrofolate reductase. therefore preventing fromation of foilates etc

ADRS of Anti-Metabolites Agents

• Methotrexate toxity:

Antidote for this toxicity: Leuvovorin: supplie the necessary cofactor of DNA

F- Fluorouracil

• For treatment of gut mucosa: Can be high or low

Purine Antagonist

• For treatment for leukemia