This article provides a note on anti cancerous drugs.
Definition:
Neo (Greek) mean new or plus and plasm mean growth. Neoplasm represents a pathologic over growth of tissue formed as a result of abnormal excessive, uncoordinated, autonomous and purposeless proliferation of cells which competes for metabolic substances with normal cells. Anti cancer drugs are agents that are used to kill/modify or arrest growth of tumor cells.
Genesis of Neoplasm:
It is a multistage process, may be associated with genetic and or epigenetic factors (hormone, co-carcinogen etc.) which may not be the primary culprit as such but may likely be inducing change in DNA, ultimately culminate into neoplasm.
This change in DNA may be brought about by:
(i) Inactivation/mutation/loss of tumor suppressor oncogenes,
(ii) Activation of proto-oncogenes which normally control cell division differentiation and gets transformed into oncogenes,
(iii) Over expression of bcl-2 genes (translocated in nodular non Hodgkins lymphoma) inactivates the key pathway of programmed cell death i.e. apoptosis,
(iv) Enzyme Telomerase when remain un-expressed in the end (i.e. telomeres’ tail) confer it senescent. But if this telomerase is expressed (observed commonly in malignant cells’ chromosome) render cancer cells immortal.
Any of these (or combination) may render a cell rebellious and autonomous which competes for metabolic substrates with normal cells. Usually accidently invaded/surplus/abnormal/nonfunctional cells undergo programmed cell death, observed as regression of uterine muscle after pregnancy, mature RBC, shedding of GIT mucosa etc.
But when the cell escape/resist/rebel apoptosis (due to anti-apoptotic genetic lesion), facilitates cancer to develop. These developments seek nutrient supply which needs fresh angiogenesis under the influence of growth factor, later metastasis and development of secondary tumor.
Characteristics of Neoplasm:
(i) Uncontrolled proliferation
(ii) Dedifferentiation
(iii) Loss of function
(iv) Invasiveness
(v) Metastasis.
(vi) Shift of cellular metabolism
Difference between cancer & bacterial chemotherapy:
Cancer chemotherapy
limited, selectivity as
Very limited immunological
(by Interferon & logical arsault TNF)
Bacterial chemotherapy
More selectivity being from host cells.
Stiffer immunodefense
Principle of cancer Chemotherapy:
(a) Cell cycle and chemotherapy.
(b) Combinational chemotherapy.
(c) Toxicity associated with anticancer drugs.
(d) Clinical usage.
(e) Resistance of tumor cells to cytotoxic drugs.
(a) Cell cycle and Chemotherapy:
Two major groups of anti-cancerous agents are used for this purpose:
I. Cell Cycle Phase Non Specific Drugs:
This include Alkylating agents, Nitrosoureas, antitumor antibiotics, Procarbazine, cisplatin, dacarbazine etc. These drugs acts on all stages of the actively proliferating cells but rarely affect cells in Go phase.
These drugs are effective for slow growth fraction (i.e. solid tumor) as well as rapidly growing tumor. The cell kill is positively co-related with the increasing doses and dose response curve follows first order kinetics i.e. a certain position/fraction of cells present are killed by one treatment.
II. Cell Cycle Phase Specific Drug:
It has been observed that these phase specific drugs yield good result only in rapidly dividing cells (5% of solid tumor). The drug includes methotrexate pyrimidine and purine analogue, hydroxyureas, vinca alkaloids and taxanes.
The cells in activable dormant stage e.g. G0, make cancer chemotherapy difficult, as they are nonresponsive to these drugs. This may be a reason of relapse as these activable dormant cells may starts dividing after cancer chemotherapy.
Moreover these drugs have no specific inhibitory effect on invasiveness, dedifferentiation or metastasis. These cytotoxic drugs are given in large doses (maximum tolerable) over a short period of time which yield high tumor cell kill albeit myelosuppression is quite frequent.
It has been observed that dose of cytotoxic drugs which has cell kill up to 99.9%, if used to treat a tumor with 1011 cells, 10 million cells will escape. Unlike microbes which then ambushed by immunological defense, these surviving tumor cells soon will pose life threat.
One of the major set back in cancer chemotherapy is that usually a tumor becomes far advanced before being noticed. Usually a single cancer cell grows exponentially to a certain extent depending upon nutritional supply through blood, needs 30 divisions to produce a cell mass of 2 cm diameter with 109 cells may be overlooked and further 10 divisions may cost subjects (animals) survival.
(b) Combination Antineoplastic Chemotherapy:
Antineoplastic drugs are most commonly administered at predetermined intervals in several combinations at appropriate dosage rates. Combinations of cytotoxic agents with different mode of action may produce synergistic result and therefore greater cancer cell kill in comparison to use of any single agent.
Usually non phase specific drugs are considered first followed by phase specific drugs, so that cells which survive the initial assault (of non phase specific drugs) be trapped when into mitosis. Cancer chemotherapy is usually considered as adjuvant to surgery and or irradiation. It is often instituted immediately following the primary treatment even in absence of any detectable metastatic dissemination.
Toxicity Patterns Associated with Anticancer Drugs:
Antineoplastic agent commonly acts on rapidly dividing cells (e.g. bone marrow, epithelium of GIT, gonads and hair follicle) so common pattern of toxicity associated with cancer chemotherapy are:
(a) Bone marrow suppression (myelosuppression) leading to leucopenia (white cell poverty) thus susceptibility against infection.
(b) Gastrointestinal disturbances.
(c) Sterility.
(d) Teratogenicity.
(e) Alopecia.
(f) Impaired wound healing.
(g) Secondary malignancy.
(h) Renal failure/damage following rapid cell destruction with excessive purine catabolism.
(i) Tissue necrosis due to extravasation of cytotoxic drugs.
Few Toxicity Ameliorations:
1. Folinic acid rescue- Has allowed administration of 100 times dose of methotrexate i.e. improves therapeutic index of methotrexate.
2. Cystitis due to cyclophosphamide and fosphamide can be blocked by mesna (parenterally in bladder). It has – SH gr., detoxify the toxic metabolites.
3. Cytotoxic drug induced vomiting-countered by 5HT3 antagonist i.e. Odansetron.
4. Hyperuricaemia – Due to massive cell destruction → large amount of purine → excreted via urine, countered by allopurinol. Alkalinization of urine & fluid helps.
Determination of Dosage:
Due to inherent toxicity of the antineoplastic agents and their narrow therapeutic indices, dosage rates are frequently calculated based on body surface area (m2) rather than body mass. e.g.
Resistance of neoplasm to cytotoxic agents: may be due to one or combination of these factors.
I. Under therapy
II. Failure in attainment of effective drug concentration
III. Single agent chemotherapy.
IV. Deletion of activating enzyme (i.e. deoxycytidine kinase for cytosine arabinoside)
V. MDR genes over expression-P glycoproteins’ general drug efflux pump
VI. Loss of p53 suppressor oncogenes.
VII. Over expression of bcl 2 gene
VIII. Reduced growth fraction and dormant (Go) neoplasm may be more resistant.
