L14 Cancer Pharmacology

一、Cancer Biology

What is Cancer

Cancer or Neoplasm is an abnormal mass of tissue as a result of abnormal proliferation of cells.

Neo-plasm: novel swelling mass in the body

**Some neoplasms do not form a tumor**

Some blood cancers such as leukemia don’t form a tumor, it widely spread in the bloodstream and bone marrow.

What are the difference between a normal and cancer cells

1. Cell shape

Normal cells:

Committed Cells—divide only a defined number of times, and are limited in capacity for self-renewal
Specialized Cells—carry out organ function and are incapable of cell division
Restricted to its functional area

Normal and Cancer Cell Structure:

### 2. Genetic Aberrations

Genetic Aberrations

Chromosomal Translocation
Chromosomal Deletion
Gene mutation

#### Chromosomal Translocation

+ Philadelphia chromosome

## How does cancer take place (Causes of cancer)

Sex: male>women
Age: most cancers in people> 50 YO
Race
Genetic predisposition
Environment - living and warking

Chemicals
Viruses

Lifestyle—smoking, alcoholism, preserved food, BBQ…

1. Polluting Environment

Ionizing radiation

Acute leukemia
Thyroid cancer
Breast cancer
Lung cancer
Basal cell skin cancers

Chemical exposure:

azo dyes
aflatoxins
asbestos
benzene

#### Azo Dyes

synthetic colours that contain an azo group, - N=N-, as part of the structure. Azo groups do not occur naturally

Azo dyes account for approximately 60-70% of all dyes used in food and textile manufacture.

Most colored textile and leather articles are treated with azo dyes and pigments

Bladder cancer (dye factory workers, Azo dye workers still have a tremendous increase in urothelial cancer

#### Oncovirus: that induce cancers

DNA Viruses

Epstein-Barr virus → Burkitt’s lymphoma
Hepatitis B virus → liver cancer
Human papilloma viruses → cervical cancer
Human herpes virus-8 → Kaposi sarcoma

RNA Viruses

Human T lymphotrophic virus type 1 (HTLV-I), a retrovirus, → T-cell leukemia.
Hepatitis C virus → liver cancer

Lifestyles

+ Smoking + Alcoholism + Preserved food + BBQ

2. Pathogenesis of Neoplasia

Cancer development can begin with a brief exposure (hours or days) to a chemical into an activated form and the chemical need not be present ever again

However, DNA is altered via mutagens including chemical carcinogens, viruses, and radiation. This mutations is inherted by at least one cell division (intiation).

This mutation mainly lead to activation of proto-oncogene into oncogenes (leading to uncontrolled cell proliferation) and/or inactivation of tumor suppressor genes (leading to resistance to apoptosis.)

Upon exposure to other epigenetic factors (hormones, cocarcinogens, immunosuppressant…which themselves are non carcinogenic) tumor growth is promoted (promotion)

Initiation

Initiation point at which an irreversible alteration, usually genetic, is introduced into a target cell

Initiation:

is essentially irreversible
caused only by carcinogenic compounds
occurs rapidly after carcinogen exposure
alone does not result in tumor formation

Promotion

Promotion is the process whereby an initiated tissue or organ develop focal proliferations and it requires the presence of continuous stimulation.

Promotion:

reversible
acts only after exposure to an initiating agent
requires repeated administration of a promoter
is not carcinogenic in itself

Etiology and Pathogenesis of Neoplasia Initiation and Promotion

# 二、Principle and strategy for cancer therapy

Cancer Therapeutic Modalities

Name	Detail
Surgery	Isolated solid cancers
Chemotherapy	Almost all cases, in combined with other treatments. It alone cure 10-15% of all patients.
Radiation therapy	Used for half of all cases to either cure or improve the symptoms of cancer.
Palliative care	Symptom management

The log-kill hypothesis

+ 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) + More intensive and frequent treatment, with adequate (2 log kill) dosing and an earlier start is successful (i.e., kill rate > growth rate) + 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.

Treatment strategies

Surgery + Radiotherapy + Chemotherapy

Combined Chemotherapy: various classes of drugs in combination

MP: Melphalan, prednisone
VAD: Vincristine, Adriamycin, dexamethasone
CHOP: Cyclophosphomide, doxorubicin, vincristine, prednisone

Correct selection of drugs in a regimen can result in decreased development of resistance, synergistic effects and decreased toxic effects.

Drug categories:

Cell Cycle Specifc (CCS)

Category	Drugs
Antimetabolites	Capecitabine, Cytarabine, Fludarabine, 5-Fluorouracil, Gemcitabine
Antitumor antibiotic	Bleomycin
Epipodophyllotoxins	Etoposide, Teniposide
Taxanes	Docetexel, Paclitaxel
Vinca Alkaloids	Vinblastine, Vincristine

Cell Cycle NonSpecifc (CCNS)

Category	Drugs
Alkylating agents	Busulfan, Carmustine, Melphalan, Thiotepa
Anthracyclines	Daunorubucin, Doxorubicin, Idarubicin
Antitumor Antibiotics	Dactinomycin, Mtomycin
Camptothecins	Irinotecan
Platinum analogs	Cisplatin, Carboplatin

Problems associated with chemotherapy

1. Resistance to chemotherapy

Resistance to chemotherapy may develop by several mechanisms:

Decrease in the amount of drug uptake by cancer cells
- E.G. Methotrexate
Increase in the amount of drug removed by cancer cells. (Transporters=P-glycoprotein).
- E.G. Vinblastine ,doxorubicin, bleomycin ,etapsoid….
Decrease or alteration in target molecule sensitivity – this is caused by mutation in the molecule targeted by the drug
- E.G. Methotrexate,Mercaptopurine,doxorubicin
Increase in DNA repair ability of the cell via an increased expression of DNA repairing enzymes.
- E.G. Alkylating agent

Resistance Mechanisms

Alterations that affect the mechanism of action of the drugs:

increased DNA repair: crosslinking agents, bleorsycin
formation of trapping agents: crosslinking agents
changes in target proteins (esp. enzymes): drugs that prevent DNA synthesis, some natural products, signal transduction inhibitors, antibodies

Alterations that affect drug concentrations inside the tumour cell:

decreased activation of prodrugs: 5-fluorouracil, cyclophosphamide, trinotecan
increased inactivation: antimetabolites (esp. purine analogues)
decreased accumulation:
1. decreased transport into the cell: folate analogues, mechlorethamine platins
2. increased export from the cell due upregulation of efflux transporters(esp increased P-glycoprotein) natural products(esp. anthracyclines, vinca alkaloids taxanes, epipodophyllotoxins)
  - this is an important cause of multidrug resistance

The P-Glycoprotein Structure

+ Encoded by ABCB1 gene

2. Toxicity and side Effects of Antineoplastic Agents

Normal cells in the body that tend to be injured the most due to chemotherapy are those which have a high growth fraction. Those are bone marrow, GI Tract ,hair follicles, reproductive organs .Leading to the followings:

Alopecia (脱发) - hair loss
Myelosuppression (骨髓功能抑制) - bone marrow loss
Emetic potential (呕吐): disruptive to cells in stomach which causes: Nausea/vomiting
Low WBC count (低白细胞数目) - low immunity

3. Treatment-induced tumor

Many anticancer drugs are mutagens and can cause the rise of neoplasm ten or more years after the original cancer was cured

三、Anti-Cancer drugs and their Pharmacology

Why term chemtherapy

Like infective disease

Some malignant cells can be cultured
Some malignancies can be transmitted by innoculation

Cancer chemotherapy not as successful as antimicrobial chemotherapy

Metabolism in parasite differs qualitatively from host cells, while metabolism in cancer cells differ only quantitatively from normal host cells

Hence target selectivity is more difficult in cancer
cancer there is no substantial immune response
Diagnostic complexity: delay in institution of treatment

Cancer cells differ from normal cells by

Uncontrolled proliferation
De-differentiation loss of function
Invasiveness
Metastasis

Cell Cycle and Cancer

The cell cycle and Cancer: both Normal and Cancer cells must traverse before and after cell division.

Classification of Anti-Cancer Drugs

1. Overall classifications

Category	Drugs
Alkylating Agents	Cyclophosphamide, Nitrosourea, Platinum analogs: Cisplatin, Carboplatin
Antimetabolites	Cytarabine, Fludarabine, Methotrexate
Plant alkaloids	Camptothecins, Etoposide, Paclitaxel, Vinblastine
Antitumor antibiotics	Bleomycin, Doxorubicin, Mitomycin
Hormonal Agents	Flutamide, Leuprolide,Tamoxifen
Differential Inducer	Arsenic trioxide, Retinoic acid derivatives
Gene targeted drugs	Cetuximab, Dasatinib, Gefitinib, Imatinib
Immunomodulators	Including cytokines and growth factors
Antiangiogenesis drugs	sorafenib, sunitinib, pazopanib

2. Polyfunctional Alkylating Agents

Introduction and classification

Alkylation is the transfer of an alkyl group from one molecule to another.

An **alkylating antineoplastic agent** is an alkylating agent used in cancer treatment that attaches an alkyl group (CnH2n+1) to DNA, especially on the guanine base of DNA, at the number 7 nitrogen atom of the purine ring

Alkylating agents classification:

| Categories | Drugs | | ----------------- | --------------------------------------------------------- | | Nitrogen mustards | Mechlorethamine,Melphalan,Cyclophosphamide,Chlorambu cil | | Ethyleneimines | Thiotepa | | Nitrosoureas | Carmustine,Lomustine | | Alkylsulfonates | Busulphan | | Platinum | Coordination complexes: Cisplatin,Carboplatin,Oxaliplatin |

Structures of alkylating agents

#### Alkylation: Mechanisms

Attach an alkyl group to various cellular constituents:

DNA—the major attacking subjects: Guanine (N7) , Adenine (N1, N3), Cytosine (N3) and Guanine (O6).
Proteins in various groups, including:
- Sulfhydryl
- Hydrocyl
- Phosphate group
- Amino
- Carboxyl
Carbomoylation of lysine residues by nitrosourea through formation of isocyanates.
Non cell cycle specific, but preferentially attack cells at late G1 and S phases, thus blocking cells at G2

Mechanisms of Alkylation of DNA Guanine

#### Mechanisms of Alkylating Action in DNA

Resistance to Alkylating agents

Acquired resistance

Increased capability to repair DNA lesions
Decreased transport of the alkylating drug into the cell
Increased production of glutathione and glutathione-associated proteins, which are needed to conjugate the alkylating agent, or increased glutathione S-transferase activity, which catalyzes the conjugation.

3. Platinum Analogs

1. Inorganic metal complex 2. They kill tumor cells in all stages of the cell cycle 3. Bind DNA through the formation of intrastrand and interstrand cross-links 4. Leading to inhibition of DNA synthesis and function. 5. N7 Guanine, N3 Adenine,O6 cytosine can also occur. 6. Nephrotoxicity acould be attenuated by i.v. saline infusion. 7. Used for NSCLC, GU, gastric, head and neck, ovarian and bladder cancers 8. Synergistic with other anticancer agents :Alkylating agents, taxanes

4. Antimetabolic Agents

Structural analogues: Neoplastic cells’ metabolic differences – increased susceptibility to actions of antimetabolites.
Most antimetabolites interfere with nucleic acid synthesis or nucleotide synthesis.
Folic acid antagonist: methotrexate, pemetrexed
Purine Antagonists: 6-Thiopurines, Fludarabine,
Pyrimidine Antagonists: 5-Fluorouracil, Cytarabine, gemcitabine
DNA synthesis (S phase–specific)

Methotrexate

**Method of action:**

1. binds with high affinity to the active catalytic site of DHFR. 2. interfering with the synthesis of tetrahydrofolate (THF) 3. THF for de novo synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine. 4. DNA, RNA, and key cellular proteins

5-Fluorouracil

Uridine derivatives
One derivative, 5-fluoro-2’-deoxyuridine 5’-phosphate (FdUMP),inhibits thymidylate synthase and its cofactor,a tetrahydrofolate derivative,resulting in inhibition of thymidine nucleotide synthesis.
Another derivative, 5-fluorouridine triphosphate is incorporated into RNA, interfering with RNA function.
Cytotoxicity: effects on both RNA and DNA

Cytarabine (ara-C)

IV administration

S phase specificity: highly schedule-dependent

Clinical Use: almost exclusively for acute myelogenous leukemia

MOA

S phase-specific antimetabolite
Biotransformed to active forms: ara-CTP, competitive inhibitor of DNA polymerase.
Blocks DNA synthesis; no effect on RNA or protein synthesis cytarabine incorporated into RNA and DNA – interfering with chain elongation

AE (side effect):

nausea, alopecia stomatitis , severe myelosuppression

5. Natural Products for Cancer Chemotherapy: Plant Alkaloids

function can be totally different

Example: Vincristine, vinblastine, Etoptosides, Camptothecin, Taxanes: Paclitaxel, Doxetaxel

Alkaloid, any of a class of naturally occurring organic nitrogen-containing bases

vinblastine and vincristine

Resource: plant products, from periwinkle plant—vinca rosea

Function:

+ **inhibition of tubulin polymerization**, which disrupts assembly of microtubules, an important part of the cytoskeleton and the mitotic spindle. This inhibitory effect results in mitotic arrest in metaphase, bringing cell division to a halt, which then leads to cell death.

Applications:

Vinblastine
- Cure for:
  - Hodgkin’s lymphoma
  - Non-Hodgkin’s lymphoma
  - Breast cancer
  - Germ cell cancer
- AE:
  - Nausea and vomitting
  - bone marrow suppression
  - alopecia

Camptothecins: Topotecan, Irinotecan

Resource: camptotheca acuminata tree

MOA: inhibition of topoisomerase I, the key enzyme responsible for cutting and religating single DNA strands –DNA damage

Indications（适应症）:

Topotecan (拓扑替康)–2nd line therapy for: Advanced ovarian cancer, small cell lung cancer
Irinotecan (伊立替康；依立替康；抗癌妥)—metastatic colorectal cancer as a monotherapy who has failed to 5-FU. Or used as 1st line in combination with 5FU and leucovorin

AE: myelosuppression and diarrhea

Taxanes, Taxol

+ Paclitaxel

#### The PK&PD of Taxol

Administration

Intravenous(135～350 mg/m2, 3h or 24h)
Intraperitoneal(60～65 mg/m2, every week)
Lipid-soluble
MW=853.91

Distribution

Liver, lung, pancreas, salivary glands, stomach, heart, muscle, kidney, etc.
Couldn’t pass the blood brain barrier

Elimination

Cytochrome P450 occur(CYP2C&CYP3A)
Form 6α-hydroxylated paclitaxel

Half-Life Elimination

Children: 4.6 to 17 hours (varies with dose and infusion duration)

Adults:

3-hour infusion: Mean (terminal): ~13 to 20 hours
24-hour infusion: Mean (terminal): ~16 to 53 hours

#### Mechanism&Usage

Paclitaxel is one of several cytoskeletal drugs that target tubulin. Paclitaxel-treated cells have defects in mitotic spindle assembly, chromosome segregation, and cell division.

Unlike other tubulin-targeting drugs, such as colchicine, that inhibit microtubule assembly, paclitaxel stabilizes the microtubule polymer and protects it from disassembly.

Usage

Anal cancer, advanced
Bladder cancer, advanced or metastatic
Breast cancer, adjuvant treatment
Breast cancer, metastatic or relapsed
Cervical cancer, advanced
Endometrial cancer, advanced or recurrent
Esophageal cancer, metastatic or unresectable locally advanced
Esophageal/esophagogastric cancer, preoperative chemoradiation
Gastric cancer, metastatic or unresectable locally advanced
Head and neck cancers, advanced
Kaposi sarcoma, AIDS related
Melanoma, advanced or metastatic
Non-small cell lung cancer
Ovarian cancer, advanced
Penile cancer, metastatic
Small cell lung cancer, relapsed/refractory
Soft tissue sarcoma (angiosarcoma), advanced/unresectable
Testicular germ cell tumors, relapsed/refractory
Thymoma/thymic carcinoma, advanced
Thyroid cancer, anaplastic
Unknown primary adenocarcinoma

Side effects

Anaphylaxis

Alopecia, headache, edema, weakness, etc

9. Natural Products for Cancer Chemotherapy: Anti-tumor antibiotics

From microbes: Streptomyces (链霉菌属)

Example:

Anthracyclines: doxorubicin, daunorubicin
Mitoxantrone, Dactinomycin
Mitomycin
Bleomycin

MOA:

Bind to DNA through intercalation between specific bases and block the synthesis of RNA, DNA, or both

Cause DNA strand scission; and interfere with cell replication

Include the anthracyclines, bleomycin, and mitomycin

Anthracyclines

Inhibition of topoisomerase II;
high-affinity binding to DNA through intercalation, with consequent blockade of the synthesis of DNA and RNA, and DNA strand scission;
generation of semiquinone free radicals and oxygen free radicals through an iron-dependent, enzyme-mediated reductive process;
binding to cellular membranes to alter fluidity and ion transport

Indications

Doxorubicin—Most used one
- Solid cancers : breast, endometrium, ovary, testicle, thyroid, stomach, bladder, liver, and lung
- Soft tissue sarcomas
- Childhood cancers, including neuroblastoma, Ewing’s sarcoma, osteosarcoma, and rhabdomyosarcoma
- Hematologic malignancies
  - acute lymphoblastic leukemia
  - multiple myeloma
  - Hodgkin’s and non-Hodgkin’s lymphomas
Daunorubicin—First identified one
- Acute myeloid leukemia.
- Limited for solid tumors

Mitomycin C

MOA

Metabolic activation through an enzyme-mediated reduction;
An alkylating agent that cross-links DNA
- Active for all cell cycles.

Used in combination with radiotherapy:

Hypoxic tumor stem cells , the most sensitive one to MMC.
Squamous cell cancer of the anus
Squamous cell carcinoma of the cervix
Breast, gastric, and pancreatic cancer.
Superficial bladder cancer–intravesical treatment while no systemic toxicity

Bleomycin

Features:

Glycopeptide antibiotics isolated from Streptomyces verticillus.
Contains a DNA-binding region and an iron-binding domain

MOA:

Binding to DNA, which results in single-stranded and double-stranded breaks following free radical formation
Inhibition of DNA biosynthesis.
DNA fragmentation is due to oxidation of a DNA-bleomycin-Fe(II) complex , which leads to chromosomal aberrations

Bleomycin is a cell cycle-specific drug that causes accumulation of cells in the G2 phase of the cell cycle

Indications:

Hodgkin’s and non-Hodgkin’s lymphomas
Germ cell tumor, head and neck cancer, and squamous cell cancer of the skin, cervix, and vulva.

Hormonal Agents

Estrogen inhibitors: Tamoxifen-antiestrogen, for breast cancer, endometrial cancer

Androgen inhibitor:

Flutamide—binds to Androgen receptor; Prostate cancer
Bicalutamide

(1) Tamoxifen

Binds to the ER of the breast tumor
Competitive inhibitor of the ER
Suppresses IGF1 and TGF-β
Therapies for: breast cancer, earlier or metastatic
Prevention for: Breast cancer

### 10. Molecularly Targeted Anti-cancer Drugs

PI3K-AKT Signaling

PI3K Pathway Inhibitors：

Genetic Aberrations

##### (1) Imatinib (Gleevec)

**MOA**: inhibition of the tyrosine kinase Bcl/ABL, prevents its phosphorylation by ATP.

Indications:

Approved for Ph+ chronic phase of CML (chronic myeloid leukemia),balst crisis that ahs progressed on prior interferon α
Gastrointestinal stromal tumors expressing the c-kit tyrosine kinase

(2) Dasatinib (Sprycel)

Crystal structure of Abl kinase domain (blue) in complex with dasatinib (red).

The main targets: BCR/ABL, Src, c-Kit, ephrin receptors, and several other tyrosine kinases, but not erbB kinases such as EGFR or Her2

Oral inhibitor
Indications: CML , ALL with Ph+
AE: Neutropenia, myelosuppression

(3) Gefitinib (Iresa) and Erlotinib (Tarcera)

Gefitinib is an EGFR (epidermal growth factor receptor) inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in target cells. Therefore, it is only effective in cancers with mutated and overactive EGFR, such as breast and lung cancers.
Is a drug used for certain breast, lung and other cancers
It is not a chemotherapeutic in the traditional sense, since it does not cause the destruction of tumor cells. Instead, gefitnib interferes with the growth and spread of new cancer cells. Anti-tumor but not cytotoxic.
Patients who don’t smoke with a bronchoaleolar subtype have a good resposiveness.
Tarcera approved for advanced pancreatic cancer in combination with gemcitabine.
AE: diarrhea, acneifrom skin rash

(4) Cetuximab

MOA:

Epidermal growth factor receptor inhibitor.
Chimeric monoclonal antibody directly against the extracellular domain of EGFR

Indications:

For metastetic colorectal cancer in combination with irinotecan or oxaliplatin.
For locally advanced head and neck cancer in combination with radiation therapy.

Proteasome and protein degradation

##### (1) Bortezomib (Velcade)

1st line for mutliple myeloma
2nd line for mantle cell lymphoma

the first and only FDA approved anti-cancer agent among proteasome inhibitors

highly selective
Reversible
26S proteasome complex
Most effective on Myeloma
Effects the bone metabolism in MM
Sensitizes them toward conventional chemotherapy
Prolongs patients’ survival by overcoming resistance to conventional drugs

Differentiation Inducers

Retinoic acid derivatives
Arsenic trioxide

Specific for APL, acute promyelocytic leukemia by induction of terminal differentiation thus losing its ability to proliferate

#### Arenic Trioxide (As2O3)

Indications: 2nd line for APL with t(15:17) translocation, refractory to ATRA or anthracyclines.

MOA:

degradation of the chimeric protein PML/RARa
mitochondria-dependent cell apoptosis

Administration: intravenous.

AE: fatigue, electrocardiographic changes (QT prolongation), arrhythmias.

Summary of Mechanisms of Action

四、Chemotherapy: Pros and Cons

A broad spectrum : almost all kinds of cancers from all organs, including Brain cancer, blood cancers, breast cancer, colon cancer, gastric cancer, lung cancer cancer, prostate cancer….

Kill cancer cells that rapidly grow, or specific genetic presented cancers

More effective when used in combination with other drugs or other methods, such as surgery or radiotherapy.

No anticancer drugs are perfect that kill cancer cells only.

Most adverse effects are:

Myelosuppression—anemia, hemorrhage, prone to infection
Somatitis
Alopecia
Gastrointestinal effects.

+ Therapeutic targeting of the hallmarks of cancer.

五、Tumor-Immuno Therapy

## Immune system and cancer

The immune system serves as one of the primary defenses against cancer. When normal tissue becomes a tumor or cancerous tissue, new antigens develop on their surface.

These antigens send a signal to immune cells such as the T lymphocytes and macrophages, which in turn directly kill the tumor cells or release substances like cytokines that may bring about tumor cell death.

## Abridged history of cancer immunotherapy: Disappointing until recently

+ 2011: Ipiliumumab shows overall survival benefit in melanoma + 2012-2014: PD1 and PD-L1 blockade has benefit in melanoma and lung + cancer 2011-2014: CAR-modified T cells show durable remissions in leukemia

Monoclonal Antibodies

Monoclonal antibodies are proteins produced in the laboratory from a single clone of a B−cell, the type of cells of the immune system that make antibodies. When used as a treatment for cancer, there are three general strategies with monoclonal antibodies:

One uses the ability of the antibodies to bind to the cancer cells having the tumor antigens on their surface. The immune system will see the cancer cells marked with bound antibodies as foreign and destroy them
A second strategy is to use the antibodies to block the binding of cytokines or other proteins that are needed by the cancerous cells to maintain their uncontrolled growth. Monoclonal antibodies designed to work like this bind to the cytokine receptors that are on the tumor cell surface.
A final strategy involves special antibodies that are linked (conjugated) to a substance that is deadly to the cancer cells. E.G. radioactive isotopes, have been successfully conjugated to antibodies. The antibodies are then used to specifically destroy he tumor cells with the radioactivity or toxic substance

Trastuzumab (曲妥珠单抗)

Trastuzumab is a humanized monoclonal antibody produced by recombinant DNA technology that binds specifically to the human epidermal growth factor receptor 2 protein (also known as HER2) that is found on the cell surface of some cancer tumors, most notably breast cancer(25−30% of breast malignancies) and also targets it for destruction by the natural killer cells of immune system.

Biological response modifiers

Researchers have been working on stimulating the immune cells during cancer with substances broadly classified as biological response modifiers. Cytokines are one such substance. These are proteins that are predominantly released by immune cells upon activation or stimulation.

Aldesleukin

Aldesleukin is interleukin, that is used to treat metastasis renal cell carcinoma (a form of kidney cancer) and metastasis melanoma. Aldesleukin is also known as interleukin−2, IL−2

Interferons

small, natural cytokines produced by leucocytes ,T−lymphocytes, and fibroblasts to activate tumor−specific cytotoxic T−lymphocytes. Thus, tumor cells would be destroyed based on immunotherapy
used to treat cancers such as hairy cell leukemia, malignant melanoma, and Kaposi’s sarcoma (an AIDS−related cancer) as well as many other cancers