Chemotherapy and the development of novel therapeutics

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1 SCPA607-Pathobiology and mechanisms of cancer Chemotherapy and the development of novel therapeutics Somphong Narkpinit, M.D. Department of Pathobiology Faculty of Science Mahidol University somphong.nar@mahidol.ac.th

2 Aim of session - Understand Cell Cycle - Chemotherapy and the cancer cell - Side effects - Administration & safety

3 Definition : Chemotherapy The treatment of cancer using specific chemical agents or drugs that are destructive to malignant cells and tissues. The term comes from two words that mean "chemical" and "treatment." Cytotoxic literally translated means toxic to cells.

4 The Cell Cycle The Cell Cycle

5 Mitosis DNA Replication Prophase Metaphase Anaphase Cytokinesis Telophase

6 A cell in mitosis Cell Biology: Mitosis

7 Normal Cell Characteristics: Metabolism. Strictly controlled & predictable Maturation & Specialisation. Occurs before dividing. Strictly controlled. Contact Inhibition. Mechanism for switching off division when in contact with different cells Recognition. Like cells stay together.

8 Cancer Cell Characteristics: Unchecked & Uncontrolled Growth Loss of contact inhibition Loss of capacity to differentiate Increased growth fraction Chromosomal Instability Capacity to metastasise Altered biochemical properties

$Growth fraction: # tumor cells$

9 Chemotherapy Drugs transported via blood Reduce size of tumor for surgical removal or for palliation Prophylaxis to prevent recurrence of cancer Growth fraction: # tumor cells undergoing mitosis

10 Chemotherapy administration Intravascular peripheral versus central lines Oral Intramuscular Intra cavity

11 Cell cycle Tumor cells similar to non-cancerous cells Neoplastic and normal cell differ in the number of cells undergoing cell division Cancer cells lack normal mechanism of suppressing cell growth Anti-cancer drugs target cells that are dividing

12 Chemotherapy Interfere with DNA, RNA, or protein synthesis S-phase specific Inhibit microtubule formation during mitosis M-phase

13 Chemotherapy Damage DNA Cell-cycle non-specific DNA alkylating agents damage tumor cells whether dividing or not

14 Combination Chemotherapy Each drug active against the cancer Different site of action Different toxicity levels If similar, toxic levels occur at different times Nadirs different times

15 Chemotherapy and Cancer Cells Cell Cycle specific : Most active against cells in a specific phase therefore need prolonged exposure or repeated doses. Cell Cycle Non-specific: Most effective against actively dividing cells but also effective in G0.

16 Chemotherapy Chemotherapy may be used conventionally to: - Cure patients - Prolong survival - Palliative care symptom control

17 Chemotherapy - Combination Therapy. - Prevents resistance. - Adjuvant Therapy. - Administered after primary therapy e.g.surgery - Neo adjuvant Therapy: Given before surgery to reduce tumour size.

18 Chemotherapy - Over 50 different chemotherapy drugs - Administered as an outpatient or inpatient depending on toxicity - Modes of administration include: Oral e.g. Methotrexate, Hydroxyurea - IV: Canula/Indwelling Central Venous Catheter - Sub cut - Intracavity e.g pelvic cavity, bladder - Intrathecal. Can be fatal if wrong drug administered!

19 Intrathecal Chemotherapy

20 Ankylating agents Mechanism of action

21 Ankylating agents Mechanism of action - Cell-cycle non-specific - Works on: - Already formed DNA - Cross-linked strands - Prevents replication

22 Alkylating Agents - Nitrogen mustard - Cyclophosphamide (Cytoxan) - Chlorambucil (Leukeran) - Cis-platin (platinol) - Ifosfamide - Dacarbazine

23 Alkylating agents - Nursing - Blood dyscrasias - Report any buzzing, ringing in ears (loss of high-freq hearing) - s/s allergic reaction

24 Alkylating agents - Nursing - Blood counts - GI mucosa nutrition important - Skin blistering - Renal/ liver function tests - Can cause sterility use contraception

25 Alkylating agents Interactions - Immunosuppressants increase infection - Anticoagulants bleeding - Digoxin decrease dig effect - Thiazides - leukopenia

26 Antimetabolites - Methotrexate - 5-fluorouracil - Cytosine arabinoside - Cytarabine (Ara-C) - Thioguanine

27 Antimetabolites - Cell-cycle specific (S-phase) - Inhibit protein synthesis - Interferes with DNA synthesis

28 Antimetabolites - Nursing - Most toxicity in hematopoietic and GI systems bone marrow stem cells and GI epithelium - Renal/ Liver function tests - s/s respiratory infection

29 Antimetabolites - Interactions - Decreases Digoxin - Affects protein bound drugs (ASA, dilantin) - NSAIDs, ASA increase toxicity - Other chemo agents/ radiation increase effect

30 Anti-Metabolite: Methotrexate - Leucovorin rescue - Form of folic acid - Treats systemic toxic effects - Administer within the first hours

31 Cytotoxic antibiotics

32 Cytotoxic antibiotics - Doxorubicin (adriamycin) - Bleomycin - Danorubicin - Idarubicin

33 Cytotoxic antibiotics - Cell-cycle non-specific - Interfere with nucleic acid synthesis - Inhibit DNA & RNA synthesis

34 Cytotoxic antibiotics - Nursing Most toxicities occur: - Hematopoietic - GI - Reproductive - Cardiac

35 Cytotoxic antibiotics - Nursing Vesicant drugs Assess: - Pain - Redness - Swelling - Ulceration

36 Cytotoxic antibiotics Interactions Digoxin decrease dig level Phenobarbital decreased chemo effectiveness Dilantin decrease dilantin level

37 Plant alkaloids

38 Plant Derivations - Periwinkle - Pacific yew - Mandrake - Campthecus acuminata Mandrake Periwinkle Pacific Yew

39 Plant alkaloids - Etopside (VP-16) - Paclitaxel (Taxol) - Vincristine (Oncovin) - Vinblastine - Vinorebline

40 Plant alkaloids - Cell-cycle specific (M-phase) - Arrest metaphase by binding to cell proteins

41 Plant alkaloids - Nursing - Check of allergies to plants prior to administration - Assess for bronchospasms - Can lower seizure threshold - Nutritional plan to combat constipation - Assess mental status depression

42 Plant alkaloids Interactions - Dependent on drug - Calcium channel blockers increase Vincristine effect - Digoxin decrease dig effect - Dilantin decrease dilantin effect

43 Chemotherapy Side Effects - Chemotherapy targets cells which are dividing rapidly. - Chemotherapy cannot distinguish between normal cells and cancer cells - Healthy Cells which have a high rate of growth and multiplication include cells of the bone marrow, hair, GI mucosa and skin.

44 Chemotherapy Side effects contd - Side effects may be drug specific e.g. anthracyclines and cardiotoxicity, vinca alkaloids and neuropathy/constipation, bleomycin and pulmonary fibrosis - Severity of side effects varies between drugs. - Side effects often occur 7-14 days post treatment.

45 Side Effects - General B bone marrow suppression A alopecia R retching F fatigue

46 Skin - Alopecia - From thin wispy pattern to total loss of hair - Hair regrows: - Thicker - Wavier - Darker color

47 Side Effects: Acute - Tumour Lysis Syndrome. - A Metabolic Emergency. - Occurrs due to rapid cell lysis (death) & large amounts of cell metabolites in blood. - If untreated can lead to acute renal failure, cardiac arrest and death.

48 Hematological - Neutropenia - Leukopenia - Thrombocytopenia - Anemia - Fatigue - Risk for infection - Risk for bleeding

49 Side Effects: Acute - Neutropenic Sepsis: - Occurs due to Bone Marrow Failure and poor immune response to infection. - Predisposing factors include: - Neutropenia - Underlying disease - Chemotherapy - Venous access devices

50 Neutropenic Sepsis - Severe overwhelming infection where inadequate blood flow to the tissues results in cellular dysfunction and, if not reversed, eventual organ failure. - Most common micro organism is gram negative - Mortality rate 40-90%

51 Side Effects: Gastro-Intestinal Nausea & Vomiting Diarrhoea & constipation Loss of appetite Taste Changes Mucositis

52 Hepatic Hepatic toxicity

53 Mucosal tissue - Stomatitis - Ulcerating lesions on mucosa - Burning sensation with fluids - Pain to oral or esophageal mucosa - Nutrition poor no appetite

54 Side Effects Example of Grade 4 Mucositis

55 Side Effects: Body Image Hair Loss Weight Loss/ Weight Gain Long term central venous catheters Skin changes (colour, rashes, sensitivity to sunshine/ chlorine, dry)

56 Neurological - Parasthesia - Motor weakness - fatigue - Paralytic ileus - Changes in hearing (high dose Cisplatin)

57 Urinary - Hemorrhagic cystitis - Renal toxicity - Purines released during cell destruction converted to uric acid crystals

58 Cardiotoxicity - Rare occurrence - Cardiac- toxicity - Pulmonary toxicity - EKG changes

60 Pulmonary Toxicity

61 Reproductive - Infertility - Cause birth defects - Cause sterility or decrease sperm

62 Emotional - Anticipatory grief - Anger - Anxiety - Depression - Guilt

63 Key Points: - Chemotherapy is a major treatment in curing or prolonging survival in cancer patients - It has a wide range of side effects depending on the drugs given. - Nurses have a key role to play in caring for a patient receiving chemotherapy - Safety issues are paramount in administration. - The potential benefit to the patient of treatment as an option must always outweigh the toxic effects

Antineoplastic Drugs. Antineoplastic Drugs. Herbal Alert. Pharmacology Chapter 51. Green tea

Antineoplastic Drugs. Antineoplastic Drugs. Herbal Alert. Pharmacology Chapter 51. Green tea Antineoplastic Drugs Pharmacology Chapter 51 Carolyn Wright, RN, BSN Ford, S. & Roach, S. (2010). Roach's introductory clinical pharmacology (9 th ed.). Philadelphia: Wolters Kluwer/Lippincott Williams