Neoplasms are carcinomas (disorderly growth of cells) that produce cancers
(tumours)
Cancer is a disease of cells where the cell is out of control, instead of reproducing in
a normal orderly manner, it multiplies gradually yet relentlessly; the excess cells thus
produced form a tumour. Eventually some of the cells spilt off spreading to other
parts of the body and create secondary cancers (metastases) which either damage
or destroy the vital organs and in most cases ultimately causes death.
Cancers can be classified into two categories
solid tumours: initially confined to a specific site but in time continue to
grow rapidly invading surrounding tissues and thus become malignant, and
liquid or haematological tumours: being involved the blood and
lymph systems are malignant from the very beginning of their origin.
Carcinogenesis is a sequential process involving
(i) initiation,
(ii) promotion (premalignancy) and
(iii) progression (malignancy and metastases)
which are primarily induced as a result of exposure to
carcinogens.
The major cancinogens that cause cancers are –
chemicals ,
radiation and
viruses.
The incidence, geography and behaviour for specific cancers are related to multiple
factors that includes- sex, age, race, genetic predisposition and exposure to
environmental carcinigens, of which last one is probably the most important.
Chemical carcinogens such as those in tobacco, azo-dyes, aflatoxins, benzene are
clearly implicated to cancer induction in humana and animals.
Certain herpes and papilloma group DNA and type C RNA viruses have also been
implicated as causative agent in animal as well as human cancers.
Oncogenic RNA viruses contain a ‘reverse transcriptase’ enzyme that permits
translation of the RNA message of tumour virus into the DNA code of the infected
cells.
A specific human T cells leukemia virus (HTLV-1) related to HIV-1 is the causative
agent for this type of leukemia
Cancers develop as a consequence of multiple changes which
activate oncogenes and
inactivate/antioncoges or tumour suppressor genes.
Each human cell contains tens of thousands (lacs) of genes and a few proto-
oncogenes (of special interest in cancer) that may be responsible cell proliferation.
On exposure to carcinogenic influences, one or more of the proto-oncogenes
activate oncogenes. Cells carrying these activated oncogenes become cancerous.
Viral oncogenes are introduced into human cells by viruses to the development of
cancers.
Absence or inactivation of anti-oncogenes or tumour suppressor genes can also
contribute to the development of cancer.
The incidence, geography and behaviour for specific cancers are related to multiple
factors that includes- sex, age, race, genetic predisposition and exposure to
environmental carcinigens, of which last one is probably the most important.
The employed modalities for controlling cancers are- prvention, early detection
and treatment. If the risk factors could be controlled/ovoided, one-third of cancer
incidence is potentially preventable. Early diagnosis and adequate therapies could
also cure at least one-third of all cancers.
The strategy for successful cancer treatment is to eliminate almost every neoplastic
cell or bring the cell number down to a level that the immune system can wipe out
the remaining cells.
The commonly used therapies for cancer treatment are- surgery, chemotherapy,
radiotherapy and immunotherapy or biotherapy.
It is observed that unexpectedly, not all are effective either singly or in combination
with most tumours. For some cancers, no therapy is effective; the majority of
metastatic cancer are not currently curable by any of the therapies.
However, it is even noted that one-third of cancer patients with the present methods
of surgery and radiation, when the tumor is localized not metastasized at the time
of treatment.
The currently employed cancer chemotherapy can be curative in certain
disseminated neoplasms that have undergone either gross or microscopice spread
such as testicular cancer, Hodgkin’s disease, choriocarcinoma and childhood
tumours (acute lymphoblastic leukemia), Burkitt’s lymphoma, Wilms’ tumor, etc.
At present, chemotherapy provides palliative rather than curative therapy for many
other disseminated cancers.
For the last decades, experimental screening and rational design of new
compounds have been employed to develop anticancer drugs. Recently,
synthesis of peptides and proteins with recombinant DNA techniques and
monoclonal antibodies have been included.
Ideal anticancer drugs would eradicate/eliminate cancer cells without harming
normal tissues. Unfortunately, none of the currently available anticancer agents
meet this criteria, and their clinical use is on basis of getting curative benefit
against toxicity.
The recent development attempts to include-
inducers of differentiation
force neoplastic cells to end-stage cells
antimetastatic drugs (designed to disturb surface properties of malignant cells)
tumor radiosensitizing and normal tissues radioprotecting
biologic response modifiers
SUGAR
N2
BASES
dr.aarif
10
Log –Kill Hypothesis
Patient with widespread cancer such as acute leukemia may have 1012 tumor
cells load in the body at the time of diagnosis.
If tolerable effective drug dose kills 99.9% of clonogenic tumor cells, this would
induce a clinical remission of the neoplasm with symptomatic improvement.
Still then there will be 109 (nine logs) cancer cells load in the body, some of
which may be inherently resistant to the drugs and some might be in the
pharmacologic sactuaries (the CNS, testes), where effective drug concentration
cannot be achieved .
(a) Infrequent treatment- prolong life but ultimately cause death
(b) Combinationation chemotherapy: if started at earlier and extensively, then
Killing of tumor cells exceeds the regrowth of tumor cells
Drug resistant does not develop
Clinical evidence of cancer is disappeared and result is cure in 1-3y
© Early surgery of primary tumor with adjuvant chemotherapy for 1y to eliminate
the remaining tumor cells result cure
The CCS drugs are used when the tumor cells are in the sensitive phase of the
cell-cycle (not in the Go)
The CCS drugs are effective because they exert action when the cells traverse
or pass through the cell-cycle and hence called CCS.
The cell-cycle non-specific (CCNS) drugs can sterile tumor cells whether they
are in the cycling or resting in Go phase.
The CCS drugs have proved most effective in hematologic malignancies and in
other tumors in which a relatively large proportion of cells are proliferating or in
the growth fraction. CCNS drugs are effective in low-growth fraction ‘solid tumor’
as well as high growth fraction tumors.
Cell Cycle–Specific (CCS) Agents Cell Cycle–Nonspecific (CCNS) Agents
Antimetabolites (S phase) Alkylating agents
Capecitabine
Altretamine
Cladribine
Bendamustine
Clofarabine Busulfan
Cytarabine (ara-C) Carmustine
Fludarabine Chlorambucil
5-Fluorouracil (5-FU) Cyclophosphamide
Gemcitabine Dacarbazine
6-Mercaptopurine (6-MP) Lomustine
Methotrexate (MTX) Mechlorethamine
6-Thioguanine (6-TG) Melphalan
Epipodophyllotoxin (topoisomerase II Temozolomide
inhibitor) (G1–S phase) Thiotepa
Etoposide Anthracyclines
Taxanes (M phase) Daunorubicin
Albumin-bound paclitaxel Doxorubicin
Docetaxel Epirubicin
Paclitaxel Idarubicin
Vinca alkaloids (M phase) Mitoxantrone
Vinblastine Antitumor antibiotics
Vincristine Dactinomycin
Vinorelbine Mitomycin
Antimicrotubule inhibitor (M phase) Camptothecins (topoisomerase I inhibitors)
Ixabepilone Irinotecan
Antitumor antibiotics (G2–M phase) Topotecan
Platinum analogs
Bleomycin Carboplatin
Cisplatin
Oxaliplatin
Classification of anticancer agents on the basis of
source and clinical use
Alkylating agents
Antimetabolites
Natural products
Miscellaneous agents
Hormones & antagonists
Antineoplastic Agents Used in the Treatment of Neoplastic Diseases
Class Agents Non-Propriotary Used in neoplastic diseases/clinical use
name
Mechlorethamine Hodgkin's disease, non-Hodgkin's lymphomas
A Nitrogen
Mustards Cyclophosphamide Acute and chronic lymphocytic leukemias, Hodgkin's disease,
L Ifosfamide non-Hodgkin's lymphomas, multiple myeloma,
K neuroblastoma, breast, ovary, lung, Wilms' tumor, cervix,
testis, soft-tissue sarcomas
Y Melphalan (L- Multiple myeloma, breast, ovary
L sarcolysin)
Chlorambucil Chronic lymphocytic leukemia, primary
A macroglobulinemia, Hodgkin's disease, non-Hodgkin's
T lymphomas
Ethylenimines Hexamethylmelamine Ovary
I
N Methylmelami Thiotepa Bladder, breast, ovary
nes
G Alkyl Busulfan Chronic granulocytic leukemia
Sulfonates
Nitrosoureas Carmustine (BCNU) Hodgkin's disease, non-Hodgkin's lymphomas, primary brain
tumors, multiple myeloma, malignant melanoma
A Lomustine (CCNU) Hodgkin's disease, non-Hodgkin's lymphomas, primary brain
G tumors, small-cell lung
Semustine (methyl- Primary brain tumors, stomach, colon
E CCNU)
N Streptozocin Malignant pancreatic insulinoma, malignant carcinoid
(streptozotocin)
T Dacarbazine (DTIC; Malignant melanoma, Hodgkin's disease, soft-tissue
Triazenes
S dimethyltriazenoimid- sarcomas
azolecarboxamide)
Antineoplastic Agents Used in the Treatment of Neoplastic Diseases
Clas Agents Non-Propriotary Used in neoplastic diseases/clinical use
s name
A Methotrexate Acute lymphocytic leukemia, choriocarcinoma, breast, head
Folic Acid
N (amethopterin) and neck, lung, osteogenic sarcoma
T Analogs
I
- Pyrimidine Fluorouacil (5-FU) Breast, colon, stomach, pancreas, ovary, head and neck,
M Floxuridine (fluorode- urinary bladder, premalignant skin lesions (topical)
Analogs
E oxyuridine; FUdR)
T Cytarabine (cytosine Acute granulocytic and acute lymphocytic leukemias
A
M arabinoside)
O Purine Mercaptopurine (6- Acute lymphocytic, acute granulocytic, and chronic
L mercaptopurine; 6- granulocytic leukemias
I Analogs
MP)
T and
E Thioguanine (6- Acute granulocytic, acute lymphocytic, and chronic
Related thioguanine; TG) granulocytic leukemias
Inhibitors Pentostatin (2'- Hairy cell leukemia, mycosis fungoides, chronic lymphocytic
deoxycoformycin) leukemia
Antineoplastic Agents Used in the Treatment of Neoplastic Diseases
Class Agents Non-Propriotary name Used in neoplastic diseases/clinical use
Vinblastine (VLB) Hodgkin's disease, non-Hodgkin's lymphomas, breast, testis
N Vinca Alkaloids
(isolated from Vinca
A rosea) Vincristine Acute lymphocytic leukemia, neuroblastoma, Wilms' tumor, rhabdomyosarcoma,
Hodgkin's disease, non-Hodgkin's lymphomas, small-cell lung
T
U Epipodo-phyllotoxins Etoposide Teniposide Testis, small-cell lung and other lung, breast, Hodgkin's disease, non-Hodgkin's
lymphomas, acute granulocytic leukemia, Kaposi's sarcoma
R Antibiotics Dactinomycin (actinomycin
A D) rhabdomyosarcoma,
Choriocarcinoma, Wilms' tumor,
L testis, Kaposi's sarcoma
Daunorubicin (daunomycin; Acute granulocytic and acute lymphocytic leukemias
rubidomycin)
P
Doxorubicin oft-tissue, osteogenic, and other sarcomas; Hodgkin's disease, non-Hodgkin's
R lymphomas, acute leukemias, breast, genitourinary, thyroid, lung, stomach, neuro-
blastoma
O Bleomycin Testis, head and neck, skin, esophagus, lung, and genitourinary tract; Hodgkin's
D disease, non-Hodgkin's lymphomas
U Plicamycin (mithramycin) Testis, malignant hypercalcemia
C Mitomycin (mitomycin C) Stomach, cervix, colon, breast, pancreas, bladder, head and neck
T
S Enzymes L-Asparaginase Acute lymphocytic leukemia
Biological Response Interferon-alfa Hairy cell leukemia, Kaposi's sarcoma, melanoma, carcinoid, renal cell, ovary, bladder,
Modifiers non-Hodgkin's lymphomas, mycosis fungoides, multiple myeloma, chronic granulocytic
leukemia
Antineoplastic Agents Used in the Treatment of Neoplastic Diseases
Class Agents Non-Propriotary name Used in neoplastic diseases
MIS Platinum Cisplatin (c/s-DDP) Testis, ovary, bladder, head and neck, lung, thyroid,
Coordination Carboplatin cervix, endometrium, neuroblastoma, osteogenic sarcoma
CELL
NE Complexes
OUS Anthracenedion e Mitoxantrone Acute granulocytic leukemia, breast
Substituted Hydroxyurea Chronic granulocytic leukemia, polycythemia vera,
AGENT Urea essential thrombocytosis, malignant melanoma
S
Methylhydrazm Procarbazine Hodgkin's disease
e Derivative (N-methylhydrazine, MIH)
Adrenocortical Mitotane (o,p'-DDD) Adrenal cortex
Suppressant Aminoglutethimide Breast
Adrenocorticost Prednisone Acute and chronic lymphocytic leukemias, non-Hodgkin's
H lymphomas, Hodgkin's disease, breast
eroids
O
Progestins Hydroxyprogesterone Endometrium, breast
R caproate
M Estrogens Medroxyprogesterone Breast, prostate
O Acetate, Megestrol acetate
N Diethylstilbestrol
E Ethinyl estradiol Breast
S Antiestrogen Tamoxifen Breast
& Androgens Testosterone propionate Breast
ANTA Fluoxymesterone
Antiandrogen Flutamide Prostate
G
Gonadotropin- Leuprolide Prostate
O
Releasing
N Hormone
ISTS Analog
DNA is the information or the coding of how everything in your body
should be built or functioned. They are passed down from parent(s)
to child to perpetuate life and the existence of their species.
In mitosis the DNA is split in half to make two complete copies of
itself. And the two copies will in turn do the same.
DNA replication is a simple and precise process that creates two
complete strands of DNA (one for each daughter cell) where only
one existed before (from the parent cell). Shortly before the cell
begins to divide, its DNA within the nucleus is “unzipped” by a
chemical called an enzyme which breaks the hydrogen bonds
between the bases.
Two halves of the DNA consequently exist. The free-floating
nucleotides within the nucleus begin bonding to the bases of both
strands. Because A only bonds with T and C only with G, both
strands form exact matches. The two are identical.
Guanine, along with adenine and cytosine, is present in both DNA and RNA,
whereas thymine is usually seen only in DNA, and uracil only in RNA. Guanine
has two tautomeric forms, the major keto form (see figures) and rare enol form.
It binds to cytosine through three hydrogen bonds. In cytosine, the amino group
acts as the hydrogen bond donor and the C-2 carbonyl and the N-3 amine as the
hydrogen-bond acceptors. Guanine has the C-6 carbonyl group that acts as the
hydrogen bond acceptor, while a group at N-1 and the amino group at C-2 act as
the hydrogen bond donor.
NUCLEOTIDES
SUGAR
N2
BASES
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26
bis (chloroethyl) amine: cyclophosphamide, chlorambucil
nitrosourea carmustin, lomustine, semustin
aziridine thiotepa
alkylsulfonate busulfan
Mechanism of action
The metabolite of cyclophosphamide (phosphoramide) crosslinks both between
and within DNA strands at guanine N-7 positions (interstrand and intrastrand
crosslinkages, respectively). This is irreversible and leads to cell apoptosis
act by exertering cytotoxic effects through transfer of their alkyl group to various cellular components
Alkylation of DNA: AAs alkylate DNA and cause cell death
react with cellular nucleophiles to make
intramolecular cyclisation to form ethyleneimonium ion or a carbonium ion &
transfer an alkyl group to the DNA on the N7 site of guanine either on a single strand or both
strands of DNA through cross-linking;
Causing Miscoding through abnormal base pairing or
Depurination by excision of of guanine
Cross-linking – responsible for cytotoxic effect &
replicating cells susceptible to AAs
Pharmacologic effects Cyclophosphamide the most useful AA.
vesicant effect
damage tissues at the site of injection
produce systemic toxicity
Toxixities induced – dose related and occur in rapidly growing tissues
bone marrow (induce supression of myelopoiesis), GI tract, gonads
IV use induce nausea and vomitting with 30-60m
Sc use produce tissue necrosis
Oral route most common, producing same effect as of the parenteral
Metoabolism
P-450 oxidase
Cyclophosphamide 4-HO-cyclophosphamide (active)
Aldophosphamide( active)
4-keto-cyclophosphamide (inactive)
Resistance If one AA becomes resistant to a tumour, then other AAs do same.
Mechanism of action
Antimetabolites exploite nucleotide and nucleic acid synthesis.
inhibit an enzyme that catalyzes pathways leading to cell replication.
Methotrexate
Methotrexate is antifolate.
It binds to dihydrofolate reductase (DHFR)
interfering with the synthesis of trihydrofolate reductase (THFR).
Lack of THFR interrupts synthesis of thymidylate, purine nucleotide, serine, methionine
thereby interfere with the formation of DNA, RNA and proteins, and thus
inhibit cell replication.
The enzyme binds methotrexate extremely tight , and at pH 6.0 no dissociation occurs.
The polyglutamtes of methotrexate are retained by the cells longer than the methotrexate and
therefore have increased inhibitory effect on the enzymes.
Drug resistance
Tumor cell resistance to methotrexate has been attributed to
(i) decrease drug transport
(ii) altered DHFR with lower affinity to methotrexate
(iii) decreased polyglutamate formation
(iv) synthesis of increased levels of DHFR
which occurs through gene amplification, increasing in DHFR messenger RNA.
Toxicity
Hypertension,, prolonged bone marrow hypoplasia, severe myelosuppression, leukopenia,
thrombocytopenia,
Other use
use in rheumatoids arthritis
Cell division, or mitosis (normal cell division;
meiosis results in sex cells), occurs in four
phases:
1.Prophase: The chromosomes pair up. By
this time, the chromosomes have replicated
so that the parent cell has two complete
sets. The cell forms two poles and the
nucleus disappears.
2. Metaphase: The chromosomes align at
the equator between both poles.
3. Anaphase: The chromosomes divide,
one of each copy heading toward each
pole. The cell membrane begins to divide.
4. Telophase: Nuclei appear at either pole
and the membrane divides. Two cells exist,
each with identical chromosomes .
Vinca alkaloids Vinblastine & Vincristine from Vinca rosea
Mechanism of action
binds specifically to the microtubular protein tubulin (in dimeric form)
drug-tubulin complex adds to the forming end of the microtubles to terminate
assembly &
thus depolarizes microtubules, resulting in
mitotic arrest at the metaphase
dissolution of the mitotic spindle
interfere with chromosomal segregation;
In addition to the aboves, vincristine cause
spindle poison
arrest of mitotic cycle
Uses Hodgkin's disease, non-Hodgkin's lymphomas, breast, testis, Acute lymphocytic leukemia, neuroblastoma,
Wilms' tumor, rhabdomyosarcoma, Hodgkin's disease, non-Hodgkin's lymphomas, small-cell lung.
Toxicities bone marrow depression, paralytic ileus, perpheral neuritis, muscle weakness,
alopecia, areflexia
Steroids and Antsteroiods
Asparginase
M/A
Pharmacology
Use
Toxicities
Clinical pharmacology of Cancer & Chemotherapeutic drugs
Leukomias
Lymphomas
