Anticancer drugs - drdhriti

36
Anticancer Drugs Dr. D. K. Brahma Associate Professor Department of Pharmacology NEIGRIHMS, Shillong

Transcript of Anticancer drugs - drdhriti

Anticancer DrugsDr. D. K. BrahmaAssociate ProfessorDepartment of PharmacologyNEIGRIHMS, Shillong

Advances in Cancer Chemotherapy

Treatment options of cancer:

No Treatment: Before 1940 Surgery: before 1955 Radiotherapy: 1955~1965 Chemotherapy: after 1965 Immunotherapy and Gene therapy

Goals of Therapy

Cure or induce prolonged ‘remission’ so that all macroscopic and microscopic features of the cancer disappear, though disease is known to persist - Acute Lymphoblastic Leukaemia, Wilm`s tumor, Ewing`s sarcoma etc. in children, Hodgekin`s lymphoma, testicular teratoma and choriocarcinoma

Palliation: Shrinkage of evident tumour, alleviation of symptoms and prolongation of life - Breast cancer, ovarian cancer, endometrial carcinoma, CLL, CML, small cell cancer of lung and Non-Hodgekin lymphoma

Insensitive or less sensitive but life may be prolonged - Cancer esophagus, cancer stomach, sq. cell carcinoma of lung, melanoma, pancreatic cancer, myeloma, colorectal cancer

Aim of Therapy – contd. Adjuvant therapy: One of the main basis of

treatment now For mopping up of residual cancer cells including

metastases after Surgery, Radiation and immunotherapy etc.

Routinely used now Mainly in solid tumours

Cancer Chemotherapy – 5 years survival rateChildhood Acute Lymphoblastic Leukemia

50 - 80%

Acute Adult Lymphoblastic Leukemia

20 - 60%

Childhood Acute Myeloblastic Leukemia

20 - 60%

Adult Acute Myeloblastic Leukemia

10 - 20%

Breast Cancer 5 - 20%Hodgkin’s lymphoma 40 - 80%

General Principles of Chemotherapy of Cancer1. Analogous with Bacterial chemotherapy – differences are

Selectivity of drugs is limited – because “I may harm you” No or less defence mechanism – Cytokines adjuvant now

2. All malignant cells must be killed to stop progemy – surival time is related to no. of cells that escape Chemo attack

3. Subpopulation cells differ in rate of proliferation and susceptibility to chemotherapy

4. Drug regimens or combined cycle therapy after radiation or surgery (Basis of treatment now in large tumour burdens)

5. Complete remission should be the goal – but already used in maximum tolerated dose – so early treatment with intensive regimens

6. Formerly single drug – now 2-5 drugs in intermittent pulses – Total tumour cell kill – COMBINATION CHEMOTHERAPY

COMBINATION CHEMOTHERAPY- SYNERGISTIC Drugs which are effective when used alone Drugs with different mechanism of action Drugs with differing toxicities Drugs with different mechanism of toxicities Drugs with synergistic biochemical interactions Optimal schedule by trial and error method More importantly on cell cycle specificity

Cell Cycle and Clinical Importance• All cells—normal or neoplastic—must

traverse before and during cell division• Malignant cells spend time in each

phase - longest time at G1, but may vary

• Many of the effective anticancer drugs exert their action on cells traversing the cell cycle - cell cycle-specific (CCS) drugs

• Cell cycle-nonspecific (CCNS) drugs - sterilize tumor cells whether they are cycling or resting in the G0 compartment

• CCNS drugs can kill both G0 and cycling cells - CCS are more effective on cycling cells

Cell cycle clinical importance – contd.

Information on cell and population kinetics of cancer cells explains, in part, the limited effectiveness of most available anticancer drugs

Information is valuable in knowing - mode of action, indications, and scheduling of cell cycle-specific (CCS) and cell cycle-nonspecific (CCNS) drugs

CCS – effective against hematologic malignancies and in solid tumors with large growth fraction

CCNS drugs – solid tumors with low growth fraction solid tumors

CCS drugs are given after a course of CCNS

Drugs Based on Cell Cycle CCNS: Nitrogen Mustards, Cyclphosphamide,

chlorambucil, carmustine, dacarbazine, busulfan, L-asparginase, cisplatin, procarbazine and actinomycine D etc.

CCS: G1 – vincristine S – Mtx, cytarabine, 6-thioguanine, 6-MP, 5-FU,

daunorubicin, doxorubicin G2 – Daunorubicin, bleomycin M – Vincristine, vinblastne, paclitaxel etc.

The Neoplastic Cell Burden May have up to 1012 tumor cells throughout the body at the time of death 109 (100 crore) cells at the time of diagnosis Debulking – 90% done Still 10% left i.e. 109 became108 or 10 crores (log kill = 1) There would still be up to 8 logs of tumor cells

Inherent resistance to drug, Pharmacological sanctuary (CNS and testes), G(0) cycle

An effective drug is capable of killing 99.999% tumor cells - clinical remission and symptomatic improvement (log kill 5) – still 0.001% cells

Therefore, scheduling of these agents is particularly important In common bacterial infections – host defense mechanism

Immunological Single clonogenic malignant cell – produce progeny kill host cells

10,00000000000 X 0.01/100 (0.0001) = 10,000000 = remains

The Log kill Hypothesis Relationship of tumor cell number to time of

diagnosis, symptoms, treatment, and survival Actions of CCS drugs follow first order kinetics: a

given dose kills a constant PROPORTION of a tumor cell population (rather than a constant NUMBER of cells)

Kill a constant fraction of the cells in a population, independent of the absolute number

Magnitude of a tumor cell kill is a logarithmic function: 4 log kill means reduction from1012 to 108

Approaches to Drug Treatment• DARK BLUE LINE: Infrequent scheduling of treatment courses with low (1 log kill) dosing and a late start prolongs survival but does not cure the patient (i.e., kill rate < growth rate) • LIGHT BLUE LINE: More intensive and frequent treatment, with adequate (2 log kill) dosing and an earlier start is successful (i.e. kill rate>growth rate)

• GREEN LINE: Early surgical removal of the primary tumour decreases the tumour burden. Chemotherapy will remove persistant secondary tumours, and the total duration of therapy does not have to be as long as when chemotherapy alone is used.

Clinical Considerations1. Early intensive start to the treatment is helpful2. Complete remission is the goal of chemotherapy3. Combined chemotherapy is useful - Drug regimens

or effective designing of number of cycles can reduce large tumour burden and delayed emergence of resistance

4. Combined chemotherapy can be curative when applied to minute residual tumour cell population after surgery or radiation

5. Treatment must continue past the time when cancer cells can be detected using conventional techniques

Resistance Intrinsic and Acquired Intrinsic: Some tumor types, e.g. malignant melanoma, renal

cell cancer, and brain cancer, exhibit primary resistance, i.e. absence of response on the first exposure, to currently available standard agents

Acquired: Single drug: change in the genetic apparatus of a given tumor cell

with amplification or increased expression of one or more specific genes

Multidrug resistance: Resistance to a variety of drugs following exposure to a single variety of

drug increased expression of a normal gene (the MDR1 gene) for a cell

surface glycoprotein (P-glycoprotein) involved in drug efflux

Toxicities Harmful to normal tissues too Steep dose response curve Low therapeutic index Particularly harmful to rapidly multiplying

normal tissues: GI mucosa, Bone Marrow, RE system and gonads and hair cells

Effects are in dose dependent manner

Toxicities1. Bone marrow deression – limits treatment2. Buccal mucosa erosion – due to high epithelial turnover

(stomatitis, bleeding gums)3. GIT: Diarrhoea, shedding of mucosa, haemorrhage

Nausea, vomiting – CTZ direct stimulation4. Skin: alopecia5. Gonads: oligospermia, impotence, amenorrhoea and infertility6. Lymphoreticular system: Lymphocytopenia and inhibition of

lymphocyte function – loss of host defence mechanism – susceptibility to infections

7. Carcinogenicity8. Teratogenicity and Hyperuricemia

Countering the Toxicities Intermittent therapy Folinic acid rescue Systemic Mesna (sodium-2-mercaptoethane

sulfonate) administration and irrigation by acetylcysteine – detoxify toxic metabolites

Ondansetron Hyperurecaemia: uricosuric agents like allopurinol Platelet and granulocyte transfusion Granulocyte colony stimulating factors (GM-CSF/G-

CSF) – recovery of garnulocytopenia

Anticancer Drugs

Classification According to chemical structure and sources of drugs

Alkylating Agents, Antimetabolite, Antibiotics, Plant Extracts, Hormones and Others According to biochemistry mechanisms of anticancer action:

Block nucleic acid biosynthesis Direct influence the structure and function of DNA Interfere transcription and block RNA synthesis Interfere protein synthesis and function Influence hormone homeostasis

According to the cycle or phase specificity of the drug: Cell cycle nonspecific agents (CCNSA) & Cell cycle specific agents (CCSA)

Mechanism of Anticancer Drugs Block nucleic acid (DNA, RNA) biosynthesis Directly destroy DNA and inhibit DNA

reproduction Interfere transcription and block RNA

synthesis Interfere protein synthesis and function Influence hormone homeostasis

Block nucleic acid (DNA, RNA) biosynthesisAntimetabolites: Folic Acid Antagonist: inhibit dihydrofolate reductase

(methotrexate) Pyrimidine Antagonist: inhibit thymidylate synthetase

(fluorouracil) ; inhibit DNA polymerase (cytarabine) Purine Antagonist: inhibit interconversion of purine

nucleotide (6-mercaptopurine and 6-Thioguanine) Ribonucleoside Diphosphate Reductase Antagonist:

(hydroxyurea)

Influence the Structure and Function of DNA Alkylating Agent: mechlorethamine,

cyclophosphamide, ifosfamide, chlorambucil, Mephalan, Busulfan, Nitrosoureas and Thio-TEPA

Platinum: cis-platinium, carboplatin and imatinib Antibiotic: bleomycin and mitomycin C Topoismerase inhibitor: camptothecin analogues

and podophyllotoxin and antibiotics like actinomycin D, daunorubicin and doxorubicin

Interfere Protein Synthesis Antitubulin: vinca alkaloids (vincristine and

vinblastin) and taxanes (paclitaxel and docetaxel)

Bind tubulin, destroy spindle to produce mitotic arrest Influence amino acid supply: L-asparaginase

.

Influence hormone homeostasisThese drugs bind to hormone receptors to block the actions

of the sex hormones which results in inhibition of tumor growth

Estrogens and estrogen antagonistic drug (EE, SERM-tamoxifene)

Androgens and androgen antagonistic drug (flutamide and bicalutamide)

Progestogen drug (hydroxyprogesterone) Glucocorticoid drug (prednisolone and others) Gonadotropin-releasing hormone inhibitor: nafarelin,

triptorelin aromatase inhibitor: Letrozole and anastrazole

Alkylating agents Nitrogen Mustards:

A) Mechlorethamine B) Cyclophosphamide, IsofamideC) Chlorambucil and others

Nitrosoures (carmustine) Alkyl sulfonates (Busulfan)

Alkylating AgentsMechanism of Action: Nitrogen mustards inhibit cell reproduction by binding irreversibly with

the nucleic acids (DNA) The specific type of chemical bonding involved is alkylation After alkylation, DNA is unable to replicate and therefore can no longer

synthesize proteins and other essential cell metabolites Consequently, cell reproduction is inhibited and the cell eventually dies

from the inability to maintain its metabolic functions.

Nitrogen Mustards Mechlorethamine:

Uses: Given IV Part of MOPP (Mechlorethamine – oncovine-prednisolone and

procarbazine) in Hodgekin`s lymphoma and disease ADRs: Severe Vomiting, myelo and immunosuppression Extravasation – severe local toxicity

Cycolphosphamide: Transformed into active aldophosphamide and phospharamide Administered orally Used in Hodgkin's lymphoma, breast and ovary cancers Ifosphamide has longer half life and used mainly I n testicular tumour

Nitrogen Mustards – contd. Chlorambucil: given orally, active against lymphoid

tissues (Ch. Lymphatic leukaemia and non-Hodgkin's lymphoma)

Busulfan: given orally, active against CML Carmustine: given IV, effective against brain tumors

and also in Hodgkin's lymphoma Dacarbazine: Different from other alkylating agents

– action against RNA and protein synthesis Used against Melanoma and Hodgkin's lymphoma

Antimetabolites Folic acid Antagonists: MTX Purine Antagonists: 6MP and 6TG Pyrimidine Antagonists: 5FU and cytarabineGeneral Characteristics: Antimetabolites are S phase-specific drugs that are structural

analogues of essential metabolites and that interfere with DNA synthesis.

Myelosuppression is the dose-limiting toxicity for all drugs in this class

Methotrexate – Folate Antagonist MOA:

The structures of MTX and folic acid are similar MTX is actively transported into mammalian cells and inhibits dihydrofolate

reductase the enzyme that normally converts dietary folate to the tetrahydrofolate form

required for thymidine and purine synthesis Leucovorin rescue:

Administered as a plan in MTX therapy Leucovorin (Folinic acid) is directly converted to tetrahydrofolic acid -

production of DNA cellular protein inspite of presence of MTX Used to rescue bone marrow and GIT mucosal cells

Resistance: Reduction of affinity of DHFR to MTX Diminished entry of MTX into cancer cells Over production of DHFR enzyme

Methotrexate – contd. Kinetics:

Given orally/IM /IV and also intrathecally and good oral absorption CSF entry - intrathecal

Indications: Choriocarinoma - was the first demonstration of curative chemotherapy Tumors of head and neck Breast cancer Acue lymphatic leukemia Meningeal metastases of a wide range of tumors

ADRs: 1) Myelosuppression - severe leukopenia, bone marrow aplasia, and thrombocytopenia 2) GIT disturbances 3) renal toxicity (crystalluria)

Purine Antagonists – 6MP, 6TG6-Mercapapurine (6-MP) and others Exact mechanisms of action are still uncertain –

inhibit purine base synthesis Used in childhood Acute lymphatic Leukaemia for

maintenance and remission and may also be in combination with MTX in choriocarcinoma

Metabolized by xanthine oxidase (inhibited by allopurinol) and allopurinol dose has to be adjusted to ½ or 1/4th

Well tolerated, mild myelosuppression and hepatotoxicity on long term administration

Antimetabolites (Pyrimidine Antagonists) - 5 FU MOA:

Fluorouracil is an analogue of thymine Converted to 5-fluoro-2deoxy-uridine monophosphate (5-FdUMP) 5-FdUMP inhibits thymidylate synthase and blocks conversion of

deoxyuridilic acid to deoxythymidylic acid – failure of DNA synthesis

Indications: solid tumors, especially breast, colorectal, and gastric tumors and squamous cell tumors of the head and neck

ADRs: nausea and vomiting, myelosuppression, and oral and gastrointestinal

ulceration. Nausea and vomitting are usually mild Mucosal damage and myelosuppression

Antibiotics Anthracyclines (doxorubicin and dau norubicin),

Dactinomycin, Bleomycin, and mitomycin Anthracyclines:

Enters themselves into DNA and causes DNA break Activates TopoisomeraseII and cause break in DNA strands Generates excess free radicals causing production of superoxide –

damage to DNA Known to damage cardiac cells also (unique) Resistance developes due to increased eflux of drug Uses: Doxo- Breast, ovary, lung, [prostate and acute lymphatic

leukaemia Dauno- ALL and AML

Read yourself Cisplatin and L-asparginase