1 Anti Cancer Part 1

Neoplastic disease

Term used for diseases in which abnormal cells divide without control and are able to invade other tissues due to mutations in DNA of cells

Related terms: Cyst, Tumor, Neoplasm

Cancer

An abnormal sac or closed cavity filled with liquid or semisolid matter

CYST:

mass that is observed as a lump in the body; neoplasm

TUMOR:

 “no lump still cancer”

 makes the skin on the breast look red and feel warm

 affected breast may become larger or firmer, tender, or itch

Inflammatory Breast Cancer

Signs & Symptoms of Inflammatory Breast Cancer

Sudden visible enlargemetn of breast

Discoloration of breast skin

Tenderness and pain in affected breast

Inward turning of nipple

does not invade surrounding tissues

Benign

invade & metastasize to all parts of the body, fatal, cancer

Malignant:

Steps of Malignant

METASTASIS OF CANCER CELLS

Melts the collagen and connective tissues

Capable of intravasation

Capable of extravasation

Capable of angiogenesis

Established Cancer Treatments

Surgery

Radiation Therapy

Chemotherapy

Hormone Therapy

Stem Cell tranplant

Treatment of cancer by using cytotoxic and other drugs

 Chemotherapy

GOALS OF CHEMOTHERAPY

palliation

cure

adjuvant

neoadjuvant

alleviation of symptoms; prolong life

palliation

eradication

Cure

surgery &/or radiotherapy then chemotherapy ; done after initial treatment

adjuvant

chemotherapy then surgery &/or radiotherapy

neoadjuvant:

Drug Combination increases what and decreases what

Increases efficacy, decreases toxicity

Chemotherapy Mos common side effects

Affects all rapidly proliferating cells:

 Hair loss

 Loss of appetite

 Nausea and vomiting

 Diarrhea

 Bone marrow suppression

 Fatigue

Chemotherapeutic Agents Types

Cell-cycle Specific Agents

Cell-cycle Non-specific Agents

Cell-cycle Specific Agents

• Phase-specific

• Phase non-specific

most active against cells that are in a specific phase of the cell cycle

Phase-specific agents:

 M-phase

Vinca Alkaloids

G1 Phase

Asparaginase

Prednisone

S phase

Antimetabolites

G2 phase

bleomycin

etoposide

effective while cells are in the active cycle but do not require that the cell be in a particular phase.

 Phase-Non specific agents:

 Phase-Non specific agents:

 Alkylating agents

 Antitumor antibiotics

 Cisplatin

They are effective in all phases, including G0.

Cell-cycle Non-specific Agents

Cell-cycle Non-specific Agents

Nitrosureas

Radiation

Anti-Cancer Drugs

1. Plant Alkaloids

2. Antibiotic Anticancer Agents

3. Hormonal Agents

4. Alkylating Agents

5. Antimetabolites

6. Miscellaneous Anticancer Drugs

Plant Alkaloids

Microtubule Damaging Agents

Topoisomerase inhibitors

Plant Alkaloids

Microtubule Damaging Agents:

Vinca Alkaloids

Taxanes

Topoisomerase Inhibitors:

Camptothecins

Podophyllotoxins

 Vinca rosea (Catharanthus roseus)

 Periwinkle plant

 Chichirica plant

Vinca Alkaloids

Vinca alkaloids Agents

 Vincristine, Vinblastine

 Vindesine, Vinorelbine

 M-Phase specific

 Bind to microtubules forming drug-tubulin complex

 The complex terminates the formation of microtubules by promoting depolymerization (disassembly) and preventing the “rescue”of microtubules.

 Disrupt formation of the mitotic spindle blocking chromosomal migration, and cell division.

Vinca Alkaloids

• Testicular cancer

• Side effects:

• Nausea and vomiting

• Alopecia

• Bone marrow suppression

Vinca Alkaloids

Vinblastine

• Hodgkin’s lymphoma Wilm’s tumor

• Side effects: Neurotoxicity or peripheral neuropathy

Vincristine

 Derived from:

 Western yew (Taxus brevifolia)

 European yew (Taxus baccata)

Taxanes

Taxanes Agents

 Docetaxel (Taxotere®)

 Paclitaxel (Taxol®)

 Cabazitaxel

 M-phase, late G2 phase specific

 Bind to and stabilize microtubules by enhancing tubulin polymerization
 Blocks dynamic instability by stabilizing GDPbound tubulin in the microtubules

 Forming weak polymers, clogged microtubules inhibiting cancer cell division and eventually lead to apoptosis

Taxanes

Indications:

 Ovarian cancer

 Advanced breast cancer

Adverse effects:

 Neutropenia

 Thrombocytopenia

 Peripheral neuropathy

Paclitaxel

Indications:

 Advanced Breast cancer

 Prostate Cancer

Adverse effects:

 Bone marrow suppression

Docetaxel

 Extracted from the root of mayapple (Podophyllum peltatum)

Podophyllotoxins

Podophyllotoxins Agents

 Etoposide - G2

 Teniposidelate S, early G2

Inhibits topoisomerase II - cause double-strand DNA breaks

Podophyllotoxins

 Enzymes that break, unwind and reseal tangled DNA strands which are necessary for DNA replication and RNA transcription.

 Topoisomerase I: Acts on one strand only ;

 Topoisomerase II: Acts on both strands ;

Topoisomerases

monocytic leukemia, testicular cancer, lung carcinoma

Podophyllotoxins

 Etoposide

lymphomas

Teniposide

Podophyllotoxins

 Etoposide - G2

 Teniposidelate S, early G2
SIDE EFFECTS

 Nausea and vomiting

 Alopecia

 Myelosuppression (primarily leukopenia)

 Lymphoid system toxicity

 Camptotheca acuminata

Camptothecins

Camptothecins Agents

 Topotecan

 Irinotecan

Inhibit topoisomerase I – cause single-strand DNA breaks

Camptothecins

Topotecan

 Irinotecan

Metastatic ovarian cancer and cisplatinresistant neoplasms

AEs:

 Neutropenia, Thrombocytopenia

 Anemia, Alopecia

 Myelosuppression

 Nausea and vomiting

Topotecan

 A prodrug ; metabolized to an active topoisomerase I inhibitor, SN-38.

Irinotecan

Indication: Colon rectal cancer

 Adverse effects:

 Early and Late forms of Diarrhea:

 Early form occurs within the first 24 hrs of treatment due to cholinergic effect (tx: atropine)

 Late or delayed form: due to SN-38 which induces direct mucosal damage with water and electrolyte malabsorption (Tx: loperamide)

 Myelosuppression, Nausea and vomiting

Irinotecan

is metabolized by UDP-glucuronosyl transferase 1A1 (UGT1A1) to form an inactive metabolite

 SN-38 i

Patients with abnormalities in this UDP-glucuronosyl transferase 1A1 are highly susceptible to Irinotecan toxicity.

(Gilbert Syndrome)

Antibiotic Anticancer Agents

A. Anthracyclines

B. Dactinomycin

C. Plicamycin

D. Mitomycin

E. Bleomycin

Anthracyclines Agents

 Daunorubicin

 Doxorubicin

 Idarubicin

 Epirubicin

 Isolated from Streptomyces peucetius var caesius

 Acts on S phase

Anthracyclines

 Stabilizes / inhibits topoisomerase II after it has cut and unwinded the DNA strands for replication ; prevents topoisomerase from reattaching the broken ends of DNA

 Intercalation: Process by which drug slides between DNA base pairs causing additional DNA strand breaks

Anthracyclines Agents

 Daunorubicin

 Doxorubicin

 Idarubicin

 Epirubicin

Process by which drug slides between DNA base pairs causing additional DNA strand breaks

Intercalation

Anthracyclines

breast, ovarian, thyroid, lung cancers and acute leukemia

Doxorubicin

Anthracyclines

Acute leukemia

Daunorubicin & Idarubicin

Anthracyclines AEs

 Cardiotoxicity

 Total alopecia, Bone marrow suppression

 May cause red or orange discoloration of the urine

 Intercalation: Intercalates between adjacent guanine-cytosine base pairs. It inhibits DNA and RNA synthesis by blocking RNA polymerase

 RNA polymerase is an enzyme that is responsible for copying a DNA sequence into an RNA sequence

Dactinomycin

Indication: often used in pediatric cancers such as Wilm’s tumor (kidney CA)

Dactinomycin

Dactinomycin AEs

Bone marrow depression

 Nausea and vomiting

 Diarrhea, oral ulcers

 Alopecia

 Causes “radiation recall”

 Potent vesicant

When a person receives this drug, the skin or tissue damaged from prior radiation therapy can become red and appear damaged again.

 Hyperpigmentation and thickening of the skin

Radiation Recall

 Formerly Mithramycin

 Isolated from Streptomyces plicatus

 Indications: Testicular cancer

Plicamycin

 MOA: Binds to DNA in the presence of Mg2+ or other divalent cations , where it interrupts RNA synthesis.

 Adverse effects: Bone marrow suppression, liver toxicity, hypocalcemia

Plicamycin

 Isolated from Streptomyces caespitosus

Indications:

 Second line agent for metastatic colon cancer

 Cervical cancer (with Bleomycin and Vincristine)

 Stomach, pancreas and lung CA (with

Doxorubicin & 5-Fluorouracil)

Mitomycin

 MOA: alkylation – cross linking of DNA strands

 An alkylating agent only after it has been metabolized intracellularly.

 The metabolite, a bifunctional alkylating agent, binds to guanine residues which crosslinks DNA strands.

Mitomycin

 Routes: Topical, intravesical (small bladder

papillomas),IV

Adverse Effects:

 Severe bone marrow suppression

 Nausea and vomiting

 Anorexia

 Renal toxicity

 Interstitial pneumonitis

Mitomycin

 From Streptomyces verticillus

Indications:

 Testicular cancer (with vinblastine or cisplatin)

 Hodgkin lymphoma

 Neck, cervical carcinoma

Bleomycin

lung toxicity; also causes hyperpigmentation of the skin

Bleomycin

MOA:  Causes DNA strand breaks due to oxidation of DNAbleomycin-Fe(II) complex, producing toxic free radicals which inhibits DNA synthesis

Bleomycin

drug that have estrogen receptor agonist or antagonist properties depending on the target issue

 MOA: In the breast, all three agents have antiestrogen activity

Selective Estrogen Receptor Modulators

SERMS Agents

 Tamoxifen

 Toremifene

 Raloxifene

SERMS for hormone receptor-positive breast cancer

Tamoxifen & Toremifene

SERMs – for risk reduction for women at high risk of breast cancer

Tamoxifen & Raloxifene

SERMs for osteoporosis due to its estrogenic activity in bone

Raloxifene

SERMs AEs

 Hot flashes

 QT prolongation (Toremifene)

SERMs Precaution

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

 These agents also carry the risk for thromboembolic events

MOA: Competitively binds to the estrogen receptor on tumors ; blocking the action of estrogen to inhibit tumor growth

Estrogen Receptor Antagonist

Fulvestrant

 Indication: for hormone-positive breast cancer

 Adverse effect:

 hot flashes

 Increased liver enzymes

Estrogen Receptor Antagonist

Fulvestrant

Aromatase Inhibitors

Agents:

 Aminoglutethimide

 Anastrozole

 Letrozole

Indication: breast cancer in postmenopausal women

Aromatase Inhibitors

Aminoglutehimide

Anastrozole

Letrozole

 Inhibitor of adrenal steroid synthesis at the first step which is conversion of cholesterol to pregnenolone

 Inhibits extra-adrenal synthesis of estrone and estradiol

 Inhibits aromatase enzyme and prevent the conversion of androstenedione to estrone, and testosterone to estradiol

 Overall: inhibit estrogen formation

Aromatase Inhibitors

Aminoglutehimide

Anastrozole

Letrozole

Adverse Effects:  Decreased bone mineral density  Hot flashes, nausea  Hypercholesterolemia (Anastrozole and Letrozole)

Precautions  Do not benefit premenopausal women  May increase the risk for ischemic cardiovascular events in patients with pre-existing ischemic cardiac disease

Aromatase Inhibitors

Aminoglutehimide

Anastrozole

Letrozole

MOA:

 Initially stimulating the release of FSH and LH, followed by inhibition of the release of these hormones  reduced testicular androgen synthesis

 Potent inhibitors of gonadotropin secretion

 Long term administration results in the suppression of LH and FSH which leads to subsequent decrease in levels of testosterone, dihydrotestosterone and estrogen

Gonadotropin-releasing hormone (GNRH Agonists)

Agents: Leuprolide, Goserelin

Gonadotropin-releasing hormone (GNRH Agonists) Agents

Agents: Leuprolide, Goserelin

Responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary.

Gonadotropin-releasing hormone (GNRH

is synthesized and released from hypothalamus.

Gonadotropin-releasing hormone (GNRH

regulates the development, growth, pubertal maturation and reproductive processes of the body

FSH:

triggers production of testosterone and estrogen

 LH:

 Indications: advanced prostate cancer, advanced breast CA (Goserelin)

 Adverse effects: hot flashes, gynecomastia, sexual dysfunction, decreased bone mineral density

 Precautions:  Tumor flare: initial administration of these agents before receptor desensitization occurs, may result in increased LH and FSH release, with a transitory increase in testosterone and an exacerbation of disease ; they are often administered with antiandrogens (flutamide)  Tumor flare can also occur in breast CA patients due to increase in estrogen

Gonadotropin-releasing hormone (GNRH Agonists)

Agents: Leuprolide, Goserelin

 MOA: Blocks GnRH receptors to decrease secretion of LH and FSH resulting to a rapid androgen deprivation by decreasing testosterone production.It acts more quickly than GnRH agonists

Gonadotropin-releasing hormone (GNRH) Antagonists)

Agent: Degarelix

 Indication: advanced prostate cancer

 Adverse effects: hot flashes, weight gain

 Precaution:ADT (androgen deprivation therapy) may increase the risk for cardiovascular disease ; Does not cause tumor flare

Gonadotropin-releasing hormone (GNRH) Antagonists)

Agent: Degarelix

MOA:

 Inhibits CYP17 (17α-hydroxylase and 17,20-lyase) which will inhibit the formation of testosterone precursor

 CYP17 is required for androgen biosynthesis

Androgen Synthesis Inhibitors

Agents: Abiraterone, Ketoconazole