Anticancer drugs: Classification , general toxicity and Alkylating agents.

Neoplasm or cancer is one of the dangerous condition. Here we discuss about cancer and it's drug classification, general toxicity and brief description about Alkylating agents.

1. ANTICANCER DRUGS :
Classification, general toxicity and
alkylating agents







Ameena kadar K A
Grace College Of Pharmacy
Palakkad

2. Cancer /Neoplasm/ Tumour;
 Neoplasm or tumour is ‘a mass of tissue formed as a result of abnormal, excessive,
uncoordinated, autonomous and purposeless proliferation of cells even after
cessation of stimulus for growth which caused it’.
 The branch of science dealing with the study of neoplasms or tumours is called
oncology (oncos=tumour, logos=study).
 Neoplasms may be ‘benign’ when they are slow-growing and localised without
causing much difficulty to the host, or ‘malignant’ when they proliferate rapidly,
spread throughout the body and may eventually cause death of the host.
 Common term used for all malignant tumours is cancer.
 The word ‘cancer’ means crab, thus reflecting the true character of cancer since ‘it sticks
to the part stubbornly like a crab’.
 All tumours, benign as well as malignant, have 2 basic components:
1) Parenchyma : comprised by proliferating tumour cells; parenchyma determines
the nature and evolution of the tumour.
2) Supportive stroma : composed of fibrous connective tissue and blood vessels; it
provides the framework on which the parenchymal tumour cells grow.
 The tumours derive their nomenclature on the basis of the parenchymal component
comprising them.
 The suffix ‘-oma’ is added to denote benign tumours.
 Malignant tumours of epithelial origin are called carcinomas, while malignant
mesenchymal tumours are named sarcomas (sarcos = fleshy).

 The anticancer drugs either kill cancer cells or modify their growth.

3.  Selectivity of majority of drugs is limited and they are one of the most toxic drugs used
in therapy.
 Treatment of malignant diseases with drugs is a rather recent development- started after
1940 when nitrogen mustard was used, but progress has been rapid, both in revealing
pathobiology of the diseases and in discovery of new drugs.
 The latest innovations target growth factors, specific signaling pathways, angiogenesis,
tumour antigens, immune therapies, etc. to introduce a different spectrum of drugs.
 Cancer chemotherapy is now of established value and a highly specialized field to be
handled by oncology specialists supported by a multidisciplinary team.
 In malignant diseases, drugs are used with the aim of:
I. Cure or prolonged remission: Chemotherapy is the primary treatment modality
that can achieve cure or prolonged remission in:
 Acute leukemias, Wilm’s tumour, Ewing's sarcoma, Retinoblastoma,
Rhabdomyosarcoma in children.
 Choriocarcinoma, Hodgkin’s disease, Lymphosarcoma, Burkitt's
lymphoma, Testicular teratomas, Seminoma, Mycosis fungoides.
II. Palliation : Gratifying results are obtained (shrinkage of evident tumour,
alleviation of symptoms) and life is prolonged by chemotherapy in: Breast cancer,
Chronic lymphatic leukemia, Ovarian carcinoma, Chronic myeloid leukemia,
Endometrial carcinoma, Non-Hodgkin lymphomas, Myeloma, Head and neck
cancer, Prostatic carcinoma, Lung (small cell) cancer.
 Many other malignant tumours are less sensitive to drugs-life may or may
not be prolonged by chemotherapy.
 Tumours that are largely refractory to presently available drugs are:
Colorectal carcinoma, Malignant melanomas, Carcinoma pancreas,
Bronchogenic carcinoma, Carcinoma stomach (non-small cell), Carcinoma-
esophagus, Renal carcinoma, Hepatoma, Sarcoma.

III. Adjuvant chemotherapy: Drugs are used to mop up any residual malignant cells
(micrometastases) after surgery or radiotherapy. This is routinely employed now
and may achieve apparent cure, especially in early breast, lung and colonic
cancers.

4. Classification of Anticancer drugs

5. General toxicity of Cytotoxic drugs
1. Bone marrow: Depression of bone marrow results in granulocytopenia, agranulocytosis,
thrombocytopenia, aplastic anaemia.
 This is the most serious toxicity; often limits the dose that can be employed.
 Infections and bleeding are the usual complications.
2. Lymphoreticular tissue: Lymphocytopenia and inhibition of lymphocyte function results
in suppression of cell mediated as well as humoral immunity.
 Because of action (I) and (2) + damage to epithelial surfaces, the host defense
mechanisms (specific as well as nonspecific) are broken down.
 Susceptibility to all infections is increased.
 Infections by fungi (Candida and others causing deep mycosis), viruses (Herpes
zoster, cytomegalovirus), Pneumocystis jiroveci (a fungus) and Toxoplasma are seen
primarily in patients treated with anticancer drugs.
3. Oral cavity: The oral mucosa is particularly susceptible to cytotoxic drugs because of high
epithelial cell turnover.
 Many chemotherapeutic drugs, particularly fluorouracil, methotrexate, daunorubicin,
doxorubicin produce stomatitis as an early manifestation of toxicity.
 The gums and oral mucosa are regularly subjected to minor trauma, and breaches are
common during chewing.
 Oral microflora is large and can be the source of infection.

6.  Neutropenia and depression of immunity caused by the drug indirectly increase the
chances of oral infections.
 Thrombocytopenia may cause bleeding gums.
 Xerostomia due to the drug may cause rapid progression of dental caries.
4. GIT: Diarrhoea, shedding of mucosa, haemorrhages occur due to decrease in the rate of
renewal of the gastrointestinal mucous lining.
 Drugs that prominently cause mucositis are- bleomycin, actinomycin D, daunorubicin,
doxorubicin, fluorouracil and methotrexate.
 Nausea and vomiting are prominent with many cytotoxic drug; this is due to direct
stimulation of CTZ by the drug, as well as generation of emetic impulses/mediators
from the upper g.i.t. and other areas.
5. Skin : Alopecia(Alopecia is the partial or complete loss of hair) occurs due to damage to the cells in
hair follicles.
 Dermatitis is another complication.
6. Gonads: Inhibition of gonadal cells causes oligozoospermia and impotence in males;
inhibition of ovulation and amenorrhoea are common in females.
 Damage to the germinal cells may result in mutagenesis.
7. Foetus: Practically all cytotoxic drugs given to pregnant women profoundly damage the
developing foetus.
 This may lead to abortion, foetal death or teratogenesis.
8. Carcinogenicity: Secondary cancers, especially leukaemias, lymphomas and histocytic
tumours appear with greater frequency many years after the use of cytotoxic drugs.
 This may be due to depression of cell mediated and humoral blocking factors against
neoplasia.
9. Hyperuricaemia: This is secondary to massive cell destruction (uric acid is a product of
purine metabolism) and is especially likely to occur in leukaemias and bulky lymphomas.
 Acute renal failure, gout and urate stones in the urinary tract may develop.
 Allopurinol is protective by decreasing uric acid synthesis.

Specific Toxicity:
 Haemorrhagic cystitis and alopecia with cyclophosphamide: Ameliorated by
administering MESNA systemically and acetylcysteine locally.
 Megaloblastic anaemia with methotrexate: Ameliorated by folinic acid/ leucovorin/
citrovorum factor.
 Nephrotoxicity with cisplatin: Saline infusion and mannitol reduce the incidence of
nephrotoxicity.
 Neuropathy with vincristine and paclitaxel.

7.  Pulmonary fibrosis and pigmentation of skin with busulfan and bleomycin.
 Cardiotoxicity with doxorubicin and daunorubicin.

 Alkylating agents:
 These compounds produce highly reactive carbonium ion intermediates which transfer
alkyl groups to cellular macromolecules by forming covalent bonds.
 The position 7 of guanine residues in DNA is especially susceptible, but other molecular
sites are also involved.
 Alkylating agents may react with carboxyl, hydroxyl, amino, sultl1ydryl and phosphate
groups of biomacromolecules.
 Alkylation results in cross linking/abnormal base pairing/scission of DNA strand.
 Cross linking of nucleic acids with proteins can also take place.
 Alkylating agents have cytotoxic and radiomimetic (like ionizing radiation) actions.
 Most agents are cell cycle non-specific, i.e. act on dividing as well as resting cells.
 Some have CNS stimulant and cholinergic properties.

8. 1. Nitrogen mustards:
 A group of alkylating agents derived from mustard gas, with the sulfur replaced by
nitrogen.
 They were formerly used as toxicants and vesicants, but now function as antineoplastic
agents.
 These compounds are also powerful mutagens, teratogens, immunosuppressants and
carcinogens.
a) Mechlorethamine (Mustine HCI):
 First nitrogen mustard
 Highly reactive and local vesicant
 Because of marked acute effects, it is no longer used
systemically.
 Mustine is now occasionally used by topical application on
cutaneous T cell lymphoma.

b) Cyclophosphamide:
 It is inactive as such: produces few acute effects and is not locally damaging.
 Transformation into active metabolites (aldophosphamide, phosphoramide mustard)
occurs in the liver, and a wide range of antitumour actions is exerted.
 It has prominent immunosuppressant property.
 Useful in many solid tumours.
 It is less damaging to platelets, but alopecia and cystitis (due to another metabolite
acrolein) are prominent.
 Dose: 2- 3 mg/kg/day oral; 10-15 mg/kg I.V. every 7- 10 days, I.M. use also possible.

9. c) Ifosphamide:
 This congener of cyclophosphamide has a longer and dose-dependent t½.
 It has found utility in bronchogenic, breast, testicular, bladder, head and neck carc-
inomas, osteogenic sarcoma and some lymphomas.
 Produces greater neurotoxicity (mental changes, hallucinations, seizures, coma) and
haemorrhagic cystis than other alkylating agents.
 To protect the bladder, MESNA ( to decrease the risk of bleeding from the bladder) ,
a - SH compound is mostly given with it.
 Mesna is excreted in urine-binds and inactivates the vasicotoxic metabolites of
ifosphamide and cyclophosphamide.
 Causes less alopecia and is less emetogenic than cyclophosphamide.
d) Chlorambucil:
 It is a very slow acting alkylating agent
 Especially active on lymphoid tissue: Myeloid tissue is largely spared.
 It is the drug of choice for long-term maintenance therapy for chronic lymphatic
leukaemia; non-Hodgkin lymphoma and few solid tumours.
 It has some immunosuppressant property.
 Dose: 4-10 mg (0. 1--0.2 mg/kg) daily for 3-6 weeks, then 2 mg daily.
e) Melphalan :
 It is very effective in multiple myeloma and has been used in advanced ovarian cancer.
 Bone marrow depression is the most important toxicity.
 Infections, diarrhoea and pancreatitis are the complications.

10.  Dore: 10 mg daily for 7 days or 6 mg/day for 2- 3 weeks-4 wceksgap-2 to4 mg daily for
maintenance orally.
f) Bendamustine :
 Indicated in chronic lymphatic leukaemia and non-Hodgkin lymphoma.
 After I.V. infusion, it is rapidly degraded with a plasma t½ of 30 min.
 Myelosuppression caused by bendamustine reverses rapidly.
 Other adverse effects are nausea, vomiting, fever, fatigue and dyspnoea.
 Dose: 100-120 mg/m2 I.V. daily for 2 days in 28 day cycles.

2. Ethylenimine:
a) Thio-TEPA:
 It is an ethylenimine
 That does not require to form an active intermediate.
 It is a stable derivative of N,N',N''- triethylenephosphoramide (TEPA).
 It is mostly used to treat breast cancer, ovarian cancer and bladder cancer.
 It is also used as conditioning for Bone marrow transplantation.
 Its main toxicity is myelosuppression.
b) Altretamine:
 It is hexamethyl melamine (HMA) which acts by alkylating DNA and proteins.
 Indicated in recurrent ovarian carcinoma for palliative treatment.
 The major toxicity is bone marrow depression and neurological effects (mental-
confusion, ataxia, hallucinations, peripheral neuritis).
 Kidney dysfunction is dose limiting toxicity.
 Dose: 260 mg/m
2
/ day oral in 4 divided doses for 2-3 weeks.

3. Alkylsulfones:
a) Busulfan:
 Highly specific for myeloid elements; granulocyte precursors being the most sensitive,
followed by those of platelets and RBC.
 It produces little effect on lymphoid tissue and GIT.
 Hyperuricaemia is common; pulmonary fibrosis and skin pigmentation are the specific
adverse effects.
 Sterility also occurs.
 It is now the 2nd choice drug to imatinib for chronic phase of myelocytic leukaemia.

4. Nitrosoureas :
 These are highly lipid soluble alkylating agents with a wide range of anti tumour activity.
 They cross blood-brain barrier- are effective in meningeal leukaemias and brain
cancer.

11.  Nausea, vomiting are common and CNS effects also occur.
 Bone marrow depression is characteristically delayed taking nearly 6 weeks to develop.
 Visceral fibrosis and renal damage can occur.
a) Carmustine:
 A cell-cycle phase nonspecific alkylating antineoplastic agent.
 It is used in the treatment of brain tumors and various other malignant neoplasms.
b) Lomustine:
 An alkylating agent of value against both hematologic malignancies and solid tumors.

5. Triazine :
a) Dacarbazine (DTIC):
 After activation in liver, it acts by methylating DNA and interfering with its function.
 Primarily used in combination regimens for Hodgkin's disease and in malignant
melanoma.
 Nausea, vomiting, flu-like symptoms, neuropathy and myelosuppression are the
prominent adverse effects.
 Dose: For Hodgkin's disease 3.5 mg/kg I.V. on day 1 and 15 of 4 weeks cycles; for
malignant melanoma 3.5 mg/kg/day I.V. for 10 days, repeat after 4 weeks.

b) Temozolomide :
 Orally active triazine methylating agent is the drug of choice for glioma and other
malignant brain tumours; also utilized in melanoma.
 Adverse effects are similar to dacarbazine.
 Dose: 100-250 mg/day.

6. Methyl hydrazine :
a) Procarbazine:
 It is not a classical alkylating agent, but has similar properties.
 After metabolic activation (it is inactive as such), procarbazine methylates and
depolymerizes DNA causing chromosomal damage.
 Inhibition of nucleic acid synthesis also occurs.
 Because of damage to DNA, mutagenic and carcinogenic potential has been detected.
 It is a component of combination regimens for Hodgkin's and related lymphomas, and is
an alternative drug for brain tumours.
 It is a weak MAO inhibitor; produces sedation and other CNS effects, and can interact
with foods and drugs.
 Alcohol causes hot flushing and a disulfiram-like reaction in patients taking procarbazine.
 Males may suffer sterility.
 Vomiting, leucopenia, thrombocytopenia are the prominent toxicities.

12.  Dose: 100 mg/m
2
/day for 14 days in 28 days cycles.

 PLATINUM COORDINATION C OMPLEXES :
 Platinum-based antineoplastic drugs (informally called platins)
are chemotherapeutic agents used to treat cancer.
 They are coordination complexes of platinum.
 These drugs are used to treat almost half of people receiving chemotherapy for cancer.
 In this form of chemotherapy, popular drugs include cisplatin, oxaliplatin,
and carboplatin.
a) Cisplatin :
 The platinum coordination complexes enter cells and are hydrolysed intracellularly
to produce a highly reactive moiety which causes cross linking of DNA.
 The favoured site is N
7
of guanine residue.
 It can also react with- SH groups of cytoplasmic and nuclear proteins.
 The effects resemble those of alkylating agents and radiation.
 It is slowly excreted unchanged in urine with a t½ of about 72 hrs.
 Negligible amounts enter brain.

13. ADR ;
 Cisplatin is a highly emetic drug; antiemetics are routinely administered before infusing
it.
 Nephrotoxicity: It can be minimized by proper hydration.
 Ototoxicity: Hearing loss can occur and is severe with repeated doses.
 Electrolyte disturbances : Hypokalaemia, hypocalcaemia and hypomagnesaemia are
common.
 Neuropathy is commonly seen with higher doses.
 Anaphylactic shock may rarely occur.
 Cisplatin has mutagenic, teratogenic and carcinogenic properties.
Uses ;
 It is very effective in metastatic testicular and ovarian carcinoma.
 Widely used in many other solid tumours; e.g. those of lung, bladder, esophagus,
stomach, liver, head and neck.
b) Carboplatin :
 It is a less reactive second generation platinum compound that is better tolerated.
 MOA and clinical utility are similar as cisplatin.
 Nephrotoxicity, ototoxicity and neurotoxicity are low.
 Nausea and vomiting is milder and is delayed; it infrequently limits the dose.
 The dose-limiting toxicity is thrombocytopenia and less often leucopenia.
 Liver dysfunction may occur.
 Because of lesser plasma protein binding, it is rapidly eliminated by the kidney with a
plasma t½ of 2-4 hour.
 It is primarily indicated in ovarian carcinoma of epithelial origin, and has shown promise
in squamous carcinoma of head and neck, small cell lung cancer, breast cancer and
seminoma.
c) Oxaliplatin :
 This third generation platinum complex differs significantly from cisplatin.
 It appears to target different biomolecules.
 Resistance does not easily develop to oxaliplatin, and it retains activity against tumours
that have become resistant to cisplatin.
 Oxaliplatin is highly effective in colorectal cancer, and 5-fluorouracil markedly
synergises with it.
 Gastroesophageal and pancreatic cancers also respond.
 The dose limiting toxicity is peripheral neuropathy.
 Sensory paresthesias involving arms, legs, mouth and throat are common.
 An acute form of neuropathy is usually triggered by exposure to cold.
 Myelosuppression is modest, but diarrhoea and acute allergic reactions are reported.
 Dose: 85 mg/m
2
I.V. every 2 weeks.

14.  REFERENCES:
 Essentials of Medical Pharmacology by K D Tripathi , 8
th
edition, Page No.915
 Pharmacology & Pharmacotherapeutics by R.S Satoskar ,Nirmala N. Rege, S.D.
Bhandarkar , 24
th
edition , Page No.1267.
 Drug Bank.