This document serves as a comprehensive research guide on cancer, detailing its incidence, pathogenesis, causes, diagnosis, treatment methodologies, and recent advances in the field. It describes different types of cancers, their pathological classification, and the biological mechanisms driving tumor growth, as well as the various approaches to treatment, including chemotherapy and targeted therapies. Additionally, it outlines future trends in cancer research aiming to improve therapeutic effectiveness and reduce toxicity.

1. RESEARCH GUIDE: RESEARCH SCHOLAR:
Dr. V. P. Rasal Miss Charu Pundir
VICE PRINCIPAL & HOD M.PHARM II YEAR
Department of Pharmacology
KLE COLLEGE OF PHARMACY, BELGAUM
OCT. 25TH 2014

2. Contents
• Introduction
• Cancer incidence
• Pathogenesis
• Causes of cancer
• Diagnosis
• Treatment
• Limitations
• Cancer models
• Cancer research organizations
• Recent advances
• Future trends
• Conclusion
• References

3. INTRODUCTION

4. Introduction
• Term neoplasia/ tumor means new growth.
• All new growth are not neoplasms as an example-
– Embryogenesis
– Regeneration and repair
– Hyperplasia &
– Hormonal stimulation
• Neoplasm or tumor is a mass of tissue formed as a result of
abnormal, excessive, uncoordinated, autonomous and
purposeless proliferation of cells.

5. Introduction
• Cancer cells are defined by 2 heritable properties-
 Reproducing in defiance of normal restraints on cell division.
 Invading & colonizing territories normally reserved for other cells.
• Clustered neoplastic tumors are benign that can be removed
surgically.
• Tumor is considered cancerous only if it is malignant, which
acquired the ability to invade surrounding tissue.
• Invasiveness usually implies an ability to break loose, enter
bloodstream or lymphatic vessels, & form secondary tumors,
called metastases.

6. Lymphoma
• Lymphoma is the most common blood cancer.
• The two main forms of lymphoma-
Hodgkin lymphoma (HL)
Non-Hodgkin lymphoma (NHL)
• Lymphoma occurs when lymphocytes, a type of white blood
cell, grow abnormally.
• Cancerous lymphocytes can travel to many parts of the body,
including the lymph nodes, spleen, bone marrow, blood or
other organs, and can accumulate to form tumors.
Introduction

7. Non-Hodgkin Lymphoma (NHL)
• Non-Hodgkin lymphoma is the most common cancer of the
lymphatic system, a part of the immune system. Broadly divided
into two major groups:
B-cell lymphomas
 T-cell lymphomas.
• B-cell lymphomas develop from abnormal B-lymphocytes and
account for 85 percent of all NHLs.
• T-cell lymphomas develop from abnormal T-lymphocytes and
account for the remaining 15 percent of all NHLs.
• Non-Hodgkin lymphomas may also be classified as-
Indolent (slow-growing)
Aggressive (fast-growing).
Introduction

8. Classification- based on origin
• Arising from epithelial cells: Carcinoma
• Arising from mesenchymal tumors: Sarcomas
• Carcinoma of Melanocytes- Melanoma
• Carcinoma of hepatocytes- Hepatoma
• Malignant tumor of lymphoid tissue- Lymphoma
• Malignant tumor of testes- Seminoma
• Cancer of blood forming cells- Leukaemia

9. Special categories of tumor
• Mixed tumors
- Adenosquamous carcinoma
- Adenoacanthoma
- Carcinosarcoma
- Collision tumour
- Mixed tumor of salivary gland
• Teratomas
• Blastomas
• Hamartoma
• Choristoma

10. CANCER INCIDENCE

11. Cancer incidence
• 8.2 million people worldwide died from cancer in 2012.
• 60% of world’s total new annual cases occur in Africa, Asia
and Central and South America.
• 30% of cancers could be prevented.
• More than 1 million new cases of cancer are diagnosed every
year in a population of 1·2 billion.
• An estimated 600 000—700 000 deaths in India were caused
by cancer in 2012
• Around 325,000 people were diagnosed with cancer in 2010
in the UK (approximately 890 people per day). More than 1 in
3 people in the UK will develop some form of cancer during
their lifetime. It remains the most common cause of death
(29%) followed by circulatory diseases(28%) such as heart
disease and strokes.

12. PATHOGENESIS

13. Pathogenesis
• Biology of tumor growth-
Malignant tumors can be divided into 4 phases:
Malignant change in target cell (Transformation)
Growth of the transformed cells
Local invasion
Distant metastasis

14. • Rates of growth
It is determined by 3 main factors:
 Doubling time of tumor cells
 Fraction of tumor cells that are in the replicative pool
 Rate at which cells are shed & lost in the growing lesion.
Pathogenesis

15. Characteristics Benign Malignant
Differentiation/anaplasia Well differentiated;
structure may be typical
tissue of origin
Some lack of differentiation with
anaplasia; structure is often
atypical
Rate of growth Usually progressive & slow;
may come to a standstill or
regress; mitotic figures are
rare & normal
Erratic & may be slow to rapid;
mitotic figures may be numerous
& abnormal
Local invasion Usually cohesive & expansile
well-demarcated masses
that do not invade or
infiltrate surrounding
normal tissues
Local invasive, infiltering the
surrounding normal tissues;
sometimes may be seemingly
cohesive & expansile
Metastasis absent Frequently present; the larger &
more undifferentiated the
primary, the more likely are
metastasis
Pathogenesis

16. Pathways of spread-
Dissemination of cancers may occur through one
of three pathways-
• Seeding of body cavities & surfaces
• Lymphatic spread
• Hematogenous spread
Pathogenesis

17. Pathogenesis
cell cycle
Growth inhibitors
(TGF-β, p53, others
Oncogenic viruses
(HPV-E7 protein; SV40-T
antigen
Growth
factors
(EGF. TGF-α,
HGF, PDGF)

18. GRADING & STAGING

19. Grading & cancer staging
• These are the systems to determine the prognosis & choice of
treatment after a malignant tumor is detected.
• Grading- cancers may be graded grossly & microscopically,
based on histology- degree of anaplasia, & the rate of growth
• Grade I: well-differentiated (less than 25% anaplastic cells).
• Grade II: Moderately- differentiated (25-50% anaplastic cells).
• Grade III: Moderately- differentiated (50-75% anaplastic cells)
• Grade IV: Poorly-differentiated or anaplastic (more than 75%
anaplastic cells).

20. • Stage 0- in situ cancer
• Stage 1- localised cancer
• Stage 2- local spread stage, usually includes spread to the
nearest lymph nodes
• Stage 3- usually indicates more extensive lymph node
involvement
• Stage 4- always indicates distant spread.
Grading & cancer staging

21. CAUSES OF CANCER

22. Causes of cancer
Any cell in the body has the potential to mutate and become a
cancer cell.
Anything that can cause cancer is termed a “carcinogen”.
Some of these include:
• Genetics
• Tobacco, smoking
• Diet deficiencies
• Racial & geographical factors
• Physical Activity
• Radiation carcinogenesis
• Non- radiation Physical Carcinogenesis
• Biologic Carcinogenesis- Parasites, Fungus, Bacteria
• Viral Carcinogenesis (introducing foreign DNA into the cell)

23. Causes of cancer

24. DIAGNOSIS

25. Diagnosis of cancer
1. Histological Methods
2. Cytological Methods
- Exfoliative cytology
- Fine needle aspiration cytology (FNAC)
3. Histochemistry & Cytochemistry
4. Immunohistochemistry
5. Electron Microscopy
6. Tumor Markers (Biochemical Assays)- Alpha-foetoprotein
(AFP), Carcino-embryonic antigen (CEA)
7. Modern Aids in Tumour Diagnosis- flow cytometry, In situ
hybridisation, Molecular diagnostic techniques, DNA
microarray analysis of tumors

26. GENERAL APPROACHES TO CANCER
TREATMENT

27. General approaches to cancer therapy
Chemotherapy
Immunotherapy
Monoclonal antibodies, cytokines,
therapeutic vaccines, the
bacterium bacillus Calmet-Guérin,
cancer-killing viruses, gene
therapy, and adoptive T-cell
transfer.
Targeted
Therapies
Transplantation
Bone Marrow
Transplantation
and Peripheral
Blood Stem Cell
Transplantation
Radiation
Therapy
Other Treatment Methods
Angiogenesis Inhibitors
Cancer Vaccines
Cryosurgery
Photodynamic Therapy

28. General approaches to cancer therapy
• Kill or remove malignant cells:
- Cytotoxic drugs
- Surgery
- Irradiation
- Targeted cytotoxic agents (e.g. antibody-linked toxins or
radioactive agents)
• Inactivate components of oncogene signaling pathway:
- Inhibitors of growth factor receptors (e.g. receptor tyrosine
kinases)
- Inhibitors of adapter proteins (e.g. Ras), cytoplasmic
kinases, cyclins, cyclin-dependent kinases, etc.
- Antisense oligonucleotides
- Inhibitors of antiapoptotic factors or stimulators of
pro apoptotic factors

29. General approaches to cancer therapy
• Restore function of tumor suppressor genes:
- Gene therapy
• Employ tissue-specific proliferation inhibitors:
- oestrogens, antioestrogens, androgens, antiandrogens,
glucorticoids, gonadotophin releasing hormone analogues.
• Inhibit tumor growth, invasion, metastasis:
- Inhibitors of angiogenesis
- Matrix metalloproteinase inhibitors
• Enhance host immune response:
- Cytokine-based therapies
- Gene therapy- based approaches
- Cell- based approaches (e.g. antitumor T cells).
• Reverse drug resistance:
- Inhibitors of multidrug resistance transport.

30. General approaches to cancer therapy

31. CANCER CHEMOTHERAPY

32. Cancer chemotherapy
 Drugs acting directly on cells (cytotoxic drugs)
1. Alkylating agents- forms covalent bonds with DNA & thus
impede replication.
Mechlorethamine, Busulfan
2. Antimetabolites- Block or subvert one or more of the
metabolic pathways involved in DNA synthesis.
Methotrexate, 6-Mercaptopurine (6-MP)
3. Vinca alkaloids- specifically affect microtubule function
Vincristine, Vinblastine

33. Cancer chemotherapy
4. Taxanes- Paclitaxel, Docetaxel
5. Epipodophyllotoxin- Etoposide
6. Camptothecin analogues- Topotecan
7. Antibiotics- Prevent mammalian cell division
Actinomycin D, Doxorubicin
8. Miscellaneous- Hydroxyurea, Procabazine

34. Cancer chemotherapy
 Drugs altering hormonal milieu-
Suppress hormone secretion or antagonize hormone action.
– Glucocorticoids- Prednisolone
– Estrogens- Fosfestrol
– Selective estrogen receptor modulators- Tamoxifen
– Selective estrogen receptor down regulators- Fulvestrant
– Aromatase inhibitors- Letrozole
– Antiandrogen- Flutamide
– 5-α reductase inhibitor- Finasteride
– GnRH analogues- Nfarelin
– Progestins- Hydroxyprogesterone acetate

35. LIMITATIONS

36. Limitations of chemotherapy
 Resistance
 Bone marrow suppression
 Lymphocytopenia
 GIT
- Stomatitis
- diarrhoea
- shedding of mucosa
- haemorrhages
 Nausea
 Vomiting
 Skin
- Alopecia
- Dermatitis
 Gonads
- Oligozoospermia
- impotence
 Teratogenesis
 Secondary cancers
 Hyperuricaemia
- Gout
- Urate stones

37. CANCER MODELS

38. Cancer In-vitro models
• In- vitro methods-
- Tetrazolium Salt Assay (Microculture Tetrazolium Test or MTT)
- Sulphorhodamine B Assay
- 3H-thymidine Uptake Assay
- Fluorescence
- Dye Exclusion Tests
- Clonogenic Assays
- Cell Counting Assay

39. MTT assay
• Developed by Mossman 1
• Cell proliferation assay
• For determination of cell growth rates
• Testing drug action
• Cytotoxic agents
• Screening biologically active compounds.
• Most rapid & large scale assay
Cancer In-vitro models

40. MTT assay
Principle:
MTT ( 3-4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
(water soluble)
Conversion
Insoluble formazen
Further solubilisation, using DMSO
Concentration determined by O.D at 570 nm
Cancer In-vitro models

41. Cancer In-vitro models
MERITS
• Less time consuming
• More cost effective
• Small quantities & large
number of compounds can
be tested.
• Easy to manage
• Can be cultured under
controlled environment (pH,
temperature, humidity, O2 ,
CO2
DEMERITS
• Furnish false positive results
& false negative results
• There is need for in-vivo
biotransformation
• Pharmacokinetics can not
be determined
• Difference lies in solid
tumor geometry of in- vivo
& in- vitro experiments.

42. Cancer In-vivo models
• In- vivo methods-
 Chemically Induced Tumor Models
 Models involving cell line /tumor pieces implantation

43.  Chemically Induced Tumor Models-
- DMBA-induced Mouse Skin Papillomas
- N-methyl, N-nitrosourea (MNU)-induced Rat Mammary Gland
Carcinogenesis
- DMBA-induced Rat Mammary Gland Carcinogenesis
- MNU-induced Tracheal Squamous Cell Carcinoma in Hamster.
Cancer In-vivo models

44. - N,N-Diethylnitrosamine (DEN)-induced Lung Adenocarcinoma
in Hamster
- 1,2-Dimethylhydralazine (DMH)-induced Colorectal
Adenocarcinoma in Rat & Mouse
- Azoxymethane (AOM)- induced Aberrant Crypt Foci in Rat
- N-Butyl-N-(4-hydroxybutyl)- nitrosamine (OH-BBN)-induced
Bladder Carcinoma in Mouse
Cancer In-vivo models

45.  Models involving cell line /tumor pieces implantation-
 Specified number of cells of a particular cell line are
inoculated into sensitive mouse strain.
 Tumors can be developed rapidly as compared to chemical
carcinogen-induced tumors
 Time saving
Cancer In-vivo models

46.  Methods involving cell line /tumor pieces implantation-
• Hollow-fiber technique
• Use of xenografts
• Nude mouse model
• Transgenic mouse model
• Newborn rat model
Cancer In-vivo models

47. Merits
• Detect host mediated
activity
• Predictive
• Estimate therapeutic ratio
• Supports in-vitro results
Demerits
• Low sensitivity
• Costly
• Time consuming
• Large number of samples are
difficult to manage
• Toxicological profile of test
drug is needed.
Cancer In-vivo models

48. Cell lines
• Dalton ascites lymphoma (DLA), Ehrlich ascites carcinoma
(EAC)
• Bladder- T24
• Breast- MCF7, MDA-MB-435
• Cervix- me-180, SIHA, HeLa
• Colon- COLO-205, HCT-15, HT-29
• Kidney- 786-0, ACHN, HEK-293
• Leukemia- U937, Raji, Jurkat
• Liver- PLC-PRF-5
• Lung- HOP-62
• Prostate- PC-3
• Melanoma- SK-MEL-2, A375
• Ovary- A2780, OVCAR-3

49. Cancer research organizations
• WHO
• Indian Cancer Society (ICS)
• Cancer aid society
• American Association for Cancer Research (AACR)
• Union for International Cancer Control (UICC)
• Indian association of cancer research
• European cancer organisation (ECCO)
• Cancer association of south africa (CANSA)

50. RECENT ADVANCES

51. Recent advances
• Circulating miRNAs: Roles in cancer diagnosis, prognosis and
therapy. 8
• Small-molecule SMAC mimetics as new cancer therapeutics. 9
• Development of new sonosensitizers for sonodynamic cancer
therapy. 10
• Potential of Cancer Cell– Derived Exosomes in Clinical
Application-The biomarkers detected in bodily fluid– derived
exosomes imply a potential for exosomes in cancer diagnosis.
It can be used as a vehicle to selectively deliver therapeutic
nucleic-acid drugs or conventional drugs for tumor therapy. 11

52. Recent advances

53. Recent advances
• Cardiac dose sparing and avoidance techniques in breast cancer
radiotherapy-
Maneuvers that displace the heart from the field such as
coordinating the breathing cycle or through prone patient
positioning
Technological advances such as intensity modulated radiation
therapy (IMRT) or proton beam therapy (PBT)
Techniques that treat a smaller volume around the
lumpectomy cavity such as accelerated partial breast
irradiation (APBI), or intraoperative radiotherapy (IORT)
Akt and p53R2, partners that dictate the progression and
invasiveness of cancer. 12

54. Recent advances
•Advanced nanovehicles for cancer management & delivery of
drug–nucleic acid combinations for cancer treatment. 13
Figure: Schematics of the preparation process of the RBC
membrane coated poly (lactic-co-glycolic) acid (PLGA)
nanoparticles (NPs)

55. Recent advances
• Types of stem cell transplants for treating cancer-
 Autologous stem cell transplants
 Tandem transplants
 Allogeneic stem cell transplants
 Mini transplants (non-myeloablative transplants)
 Syngeneic stem cell transplants – for those with an
identical sibling
 Half-matched transplants

56. Recent advances
• The p53-mediated cytotoxicity of photodynamic therapy of
cancer. 14
• “Diamond” mammoplasty as a part of conservative
management of breast cancer. 15
• Stereotactic radiotherapy (SABR) for the treatment of primary
non-small cell lung cancer. 16

57. FUTURE TRENDS

58. Future trends
• Clinical effectiveness of new drugs may improve if
developments in pharmacogenetics will be done.
• Computer-assisted surgery with three-dimensional imaging
allow the tumour and anatomy of the organ to be clearly
visible.
 Intra-operative diagnosis will also be more prevalent.
 Ultrasound scans used during surgery may show previously
undiscovered metastases, which can be dealt with
immediately.
• Efforts to mark tumours with a radioactive isotope so that a
Geiger counter passed over the body can detect distant
metastases, or with fluorescent markers that glow in the dark.

59. Future trends
• Minimization of toxicity of combination treatments.
• Elucidation & correlation of mechanism of action of individual
agents, their kinetics, pharmacologic activity, and the mode of
delivery.
• Design of delivery vectors with appropriate timing and
sequence of delivery of individual agents & combinations.
• Discovery of new drug–
 Nucleic combinations that would extend beyond the
current dominant focus on overcoming drug resistance
 Enhancing the effectiveness
 Safety of drug–nucleic acid combinations. 13

60. Future trends
• p53 is the main inducer of p53R2, in order to understand the
precise role of p53R2 and how its levels are elevated in some
cancers, it is suggested to study the ability of mutant p53 in
induction of p53R2.
• On the other hand, since p21 has dual opposite roles in
regulation of cell cycle, and p53R2 can up-regulate p21, it is
better to focus future investigation on the role of p21 in
cancer progression and its association/interactions with
p53R2.
• The need to develop novel sonosensitizers with optimal
properties for treating human cancers. 10

61. Conclusion

62. Conclusion
• Basic research in cancer biology has provided new targets for
cancer drug development & has brought older targets into
sharper focus, leading to new & novel approaches to cancer
prevention & treatment.
• Conventional methods of drug screening are continuously
being refined or replaced with newer methods & thereby
accelerating the drug development process.
• Efforts are being done to achieve specific predefined locus of
action.
• It is inevitable that in the years to come we will see high
technology, high speed, high volume & information- intensive
approaches to the identification of novel targets genes,
proteins & drugs.
• However, the importance of basic research in the molecular
biology & pharmacotherapy of cancer remains critical.

63. References

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