Neoplastic Diseases

P. Manyau
School of Pharmacy
University of Zimbabwe
Objectives
• Define cancer
• Cell cycle
• Discuss mechanisms of Carcinogenesis
• Chemical carcinogens
• Malignancies associated with infection
• Oncogenes and tumour suppressor genes
• Tumour growth
• Tumour characteristics
• Screening, diagnosis
• Treatment modalities
• chemotherapy
Surveillance and Statistics
• It’s expected that by 2020 there will be 15mil new cancer cases/year,
and 70% of them will be in developing countries (GLOBCAN 2012)
• Zimbabwe National Cancer Registry (ZNCR)
• Locally the top 5 cancers in men and women are as follows:
• Men: prostate, Karposi’s sarcoma, Non-Hodgkin’s Lymphomas, GIT and liver
• Women: Ca cervix, breast cancer, Karposi’s sarcoma, Non-Hodgkin’s
Lymphomas, GIT
• For paeds the most common cancers are as follows: Leukaemia,
Lymphomas, nephroblastoma (Wilm’s tumour), retinoblastoma, soft
tissue sarcoma
The Balancing Act
• Growth, stasis and degeneration
• Genetic mechanisms underlying
factor
• Homeostatic functions that
regulate
• Which cell type is replicated
• Time of cell death
• With age this balance is not
easily maintained
Cancer
• Cancer is a group of more than
100 different diseases
• It is characterised by
uncontrolled cell replication,
local tissue invasion and distant
metastases.

• Organ system function is

disrupted
Cell Replication
S Phase
• DNA replication
Carcinogenesis
• The mechanism by which cancer occurs is not completely understood.
• Exposure to known carcinogens does not necessarily result in cancer
• Risk factors
• Carcinogenesis is a multi-stage process that is genetically regulated
• Initiation is when exposure to a carcinogen results in damage to cells
• The damage may be repaired, however if left alone may result in irreversible
gene mutations.
• The mutated cell has an altered response to its environment with a selective
growth advantage
• Develops into a clonal population of neoplastic cells
Carcinogenesis
• The second phase is called Promotion
• It involves exposure to carcinogens or environmental factors that promote
neoplasm growth
• Initiation is reversible however promotion is not
• The body has natural repair mechanisms e.g proof reading of DNA by DNA
polymerase, lysis of neoplasm cells by cytotoxic T-cells
• It takes months to years to from the initiation to promotion stage and then
clinically detectable disease depending on the type of cancer
• Burkitt’s lymphoma, testicular and paediatric tumours are fast growing and have a
small volume doubling time
• Breast cancer, prostate cancer and colon cancer are slow growing
Carcinogenesis
• Progression : involves further
genetic changes leading to
increased cell proliferation.
• The critical element of this stage
is tissue invasion of local tissue
and development of metastases.
Carcinogens
• Exposure to chemicals may occur by virtue of occupational and environmental
means
• E.g aniline dyes, benzene some drugs and hormones, cigarette smoke contains
aromatic compounds which are carcinogenic
• Physical agents such as ultraviolet light, ionising radiation
• They form free radicals which damage DNA
• Biologic agents such as viruses
• Epstein-Barr virus is believed to be an important factor in Burkitt’s lymphoma
• HSV8 (KS), Hep B (liver carcinoma), HPV (cervical cancer)
• HIV positive patients are more likely to develop a non-AIDS defining malignancy. This is
thought to be due to chronic inflammation- some inflammatory mediators play a role
in proliferation of cancer cells
Oncogenes
• The 2 major classes of genes involved in carcinogenesis are
oncogenes and tumour suppressor genes
• Oncogenes are derived from normal genes called proto-oncogenes
• Involved in normal growth and the cell cycle. Under normal circumstances
they are only active when required
• Mutations e.g insertions, deletions or translocations result in a gene that
cannot be switched off or overexpression
• One mutation makes it easier for other mutations to occur, and
cancer cells will end up with more than one mutation
Examples of Oncogenes
• Philadelphia Chromosome: Bcr-
Abl fusion oncoprotein resulting
from a t(9:22) translocation of
Bcr gene. The fusion protein
codes for a tyrosine kinase with
constitutive activity (leukaemias)
• Bcl -2 gene is responsible for bcl-2 is a proto-
oncogene found on chromosome 18, this
gene can translocate to chromosome 14
t(14:18) (lymphomas)
Other Mechanisms
• Signal transduction via
• Increased secondary messenger
• Protein with constitutive activity
• Upregulation of growth factor
receptor or their agonists
Oncogenes
• Tumour suppressor genes regulate and inhibit irregular cell growth
• Loss of gene function via a mutation or deletion will result in uncontrolled cell
growth.
• e.g retinoblastoma gene (Rb) and p53.
• Mutation of p53 is one of the most common genetic changes associated with
cancer
• P53 is responsible for negative regulation of the cell cycle and apoptosis
• Also involved in cytotoxic effects of chemotherapy, mutations are associated with drug
resistance
• The number of genetic abnormalities contribute to prognosis and treatment
choice
Epigenetics
• Genetic changes which occur
independently of the genetic sequence
that result in altered gene transcription
• DNA methylation of cytosine rich islands
• Histone acetylation/ methylation
• Micro-RNAs
• DNA methylation and histone acetylation
alter the conformational structure of DNA
making certain genes inaccessible
(silencing)
• Normally silencing of tumour suppressor
genes e.g p15
• Multi-drug resistance protein (MDR1) coding
for P-gp drug resistance
Cervical Cancer
• This is the most common cancer
amongst Zimbabwean women
• Associated with human papilloma virus
and HIV coinfection
• Women who have CA-cervix tend to have
earlier sexual debuts
• Multiple sexual partners or a parter with
multiple sexual partners
• Cervical screening (VIAC and PAP
smears have been shown to greatly
reduce incidence)
• Precancerous lesions can be removed by
cautery or cryotherapy
Molecular Mechanism of Pathogenesis
Cervical Cancer – Lesions and Dysplasia
Karposi’s Sarcoma
• The second most common cancer
among Zimbabwean males
• It is characterised by angioproliferative
multifocal tumours on the skin mucosa
and less commonly vicsera
• It is caused by a combination of
immunodeficiency and Herpes
Simplex Virus (HSV8) infection
• HIV associated malignancy and
incidence has gone down dramatically
with access to HAART
Karposi’s Sarcoma
• Pathogenesis is the result of a complex interplay of:
• oncogenic viral proteins,
• Activation of host oncogenes
• Angiogenesis by vascular endothelial growth factor
• Inflammatory cytokines
• KS is not associated with a pattern of genetic mutations by a the
creation of a microenvironment in the host that is conducive to
neoplasm growth
Breast Cancer
Prostate Cancer - Anti-Androgen therapy
• Androgens are required for the
development of a normal prostate
and prostate cancer
• The mainstay of therapy involves
ablation of testosterone and
dihydroxytestosterone activity
• Androgen activity in the prostate
is mediated by
dihydroxytestosterone, and 5α
reductase catalyses the final step
in its synthesis
Haematological Malignancies
Lymphoid Malignancies
• Primary sites of lyphopoeisis of lymphoid cells are bone marrow and
thymus
• Secondary sites of differentiation/ maturation are lymph nodes, spleen GIT
• Manifestations of lymphoma are generally observed in the secondary sites
• There can be over proliferation of immature or mature cells
• Examples include: Hodgkin’s Disease (5 different types)
• Non-Hodgkin’s Lymphomas (NHL). Can have B-cell or T-cell, includes diffuse B-cell
large lymphoma, Burkitt’s lymphoma, follicular cell
• Acute Lymphoblastic Leukaemia – cancer of immature lymphocytes, commonly
seen in children but does occur in adults. Can be B-cell or t-cell
• Chronic lymphocytic leukaemia – occurs in elderly
Myeloid Leukaemias
• Myeloid cells are formed and
mature in the bone marrow
• Immature cells in peripheral blood
are suggest malignancy
• Bone marrow biopsy to confirm
• Examples include
• Acute myeloid leukaemia (myeloid
stem cell)
• Chronic myeloid leukaemia
(myeloblast)
• Myelodysplasic syndromes
Multiple Myeloma
• Normally presents in the elderly
• Uncontrolled replication of plasma
cells in the bone marrow
• Produce non-functional antibodies
called M-protein/ para-protein
• Calcium (hypercalcaemia)
• Renal impairment
• Anaemia
• Bone disease
Tumour Growth
• Characterised by Gompertzian growth
curve.
• In the early stages growth is exponential
i.e the tumour doubles its size at a
regular time interval
• Most chemotherapy is more effective
with smaller tumours because it act on
dividing cells
• The smaller the tumour the more actively
dividing cells the more effective the chemo.
• As the tumour grows the doubling time is
slowed, and the number of actively
dividing cells are reduced
Tumour Burden
• It takes 10⁹ cells (1gm + 1cm diameter) for a tumour to be clinically
detectable.
• Such a tumour has undergone 30 doublings, and it only takes 10 more for it to
reach 1kg
• Tumour burden also relates to response to chemotherapy
• E.g if a tumour has 1000 cells and chemotherapy kills 90%, then 100 cells
remain, and the next cycle will kill 90 cells leaving 10. it is not possible to
reach 0. Tumours with 10⁴ cells are considered to be small and the immune
system can deal with them
Tumour Characteristics
• Tumours may be benign or malignant
• Benign tumours non-cancerous and
are often encapsulated, localised and
indolent
• Seldom metastasise once removed
• The name cancer arose from the
‘claw like’ projections extending from
a central tumour (invasive disease)
• The cells are genetically unstable
• Loss of normal cell architecture results
in cells which are abnormal for their
origin
Tumour Origin
• May arise from any tissue
• -oma is generally used to denote benign tumours e.g adenoma
• Carcinomas: growths arising from epithelial cells e.g adenocarcinoma
• Sarcomas: tumours arising from muscle or connective tissue
• Haematological malignancies are classified differently
• Leukaemias
• Lymphomas
Diagnosis
• Most cancers are cureable with surgery or radiation before they have
metastasised
• Early diagnosis is difficult for most cancers because there are no
clinical signs until the have grown or metastasised
• Cost effective interventions have reduced the incidence of cancer
• E.g VIAC, breast or prostate self examination
• Diagnostic methods include:
• Scans, tissue biopsy, histology, histoimmunochemisty, tumour markers
Staging
• All tumours should be staged in order to use the proper treatment
modalities and assess response to treatment
• Surgery, radiation or chemotherapy
• Uniform staging is necessary for standardisation and comparisons of
different treatments, especially for clinical trials
• Factors that affect staging are:
• Tumour burden, presence of metastases, involvement of lymph nodes
for some tumours
• After staging goal of treatment should be determined
• Cure or palliation
Chemotherapy
• Primary induction - used when the cancer can be cured with
chemotherapy e.g haematological malignancies or when there is no
other effective approach (palliation)
• Adjuvant treatment is used to reduce incidence of local and systemic
recurrence.
• E.g when the main tumour is removed with surgery residual cells are
removed with chemotherapy
• Neoadjuvant chemotherapy is used when the other treatment option
is not completely effective
• E.g chemo/ rad, or pre-op chemotherapy