1. Cancer Chemotherapy and immunosupressants

2. Background
It is the second most common cause of death in the developed nations
One in three people will be diagnosed with cancer during their lifetime
There are approximately 200 types of cancer, each with different causes, symptoms and treatments
The terms cancer, malignant neoplasm and malignant tumour are synonymous
Cancer: is a disease in which there is uncontrolled multiplication & spread within the body of abnormal forms of body’s own cells
Cancer cells manifest, to varying degrees, four characteristics that distinguish them from normal cells:
Uncontrolled proliferation
Dedifferentiation & loss of function
Invasiveness
Metastasis

3. It is estimated that more than 1
It is estimated that more than 1.6 million new cases of cancer will be diagnosed in Prostate cancer is the most common cancer among men (26%), followed by lung (14%) and colon & rectum (8%) cancers. Among women, breast (29%), lung (13%), and colon & rectum (8%) cancers are the most common cancers.

4. Causes Oncogenes Tumour suppressor genes
A normal cell turns into a cancer cell b/c of one or more mutation in its DNA, which can be inherited or acquired through exposure to viruses or carcinogens (e.g. tobacco products, asbestos)
2 main categories of cancer genes:
Oncogenes
Tumour suppressor genes
Incidence, geographical distribution, & behaviour of specific types of cancer are related to: age, sex, race, genetic predisposition, & exposure to environmental carcinogens

5. Mutated or “activated” Tumor suppressor genes
Normal + -
Proto-oncogenes
Cell growth
and
proliferation
Tumor suppressor genes
Cancer
Mutated or “activated”
oncogenes ++
Malignant
transformation
Loss or mutation of
Tumor suppressor genes

6. Tumour suppressor gene
These genes normally function to PREVENT cell growth/division TS
Tumour suppressor genes (TSG) code for proteins that slow down cell growth. They can halt the cell growth cycle to stop unnecessary division or promote apoptosis (cell death) if the cell’s DNA is damaged.
Different tumour suppressor proteins carry out the following functions:
Repression of genes which are essential to the cell cycle, therefore inhibiting cell division.
Linking the cell cycle to DNA damage; if there is damage to the cell it will not allow it to divide.
Identifying where the DNA damage is irreparable and initiating apoptosis (cell suicide).
The animated chromosome diagram illustrates that both copies of the TSG have to be inactivated by mutation or other alteration for there to be a loss of cell cycle control. If one functional copy remains, there is still a “brake” on the cell’s growth.
The “cell as a car” analogy:
One way to think about TSGs is to see them as the brakes of a car. There is a gene on both chromosomes so in a sense there are two brakes. If one gene is mutated and its protein loses its function, the cell can still halt and prevent unregulated cell growth as the other copy of the gene (or brake) is still functioning. However if that back up copy also changes and no longer codes for a functioning protein, the cell cycle is no longer under control and this can lead to cancer.
Cancer

7. Oncogene
Genes which normally function to PROMOTE cell growth/division in a controlled manner
Ras
Proto-oncogenes code for proteins that drive cell division. When these genes acquire mutations that result in continually active proteins they become oncogenes and cause uncontrolled cell growth and division.  
The “cell as a car” analogy:
If you are using the car analogy, oncogenes can be seen as the accelerator. When one healthy copy of the proto-oncogene is altered it is the equivalent of the accelerator pedal being stuck – speeding up cell growth and division. Notice in the case of oncogenes that it only takes one copy of the gene to undergo changes to lead to cancer, rather than both copies as is the case with TSGs.
Cancer

8. The log cell kill hypothesis
Cytotoxic drugs act with first-order kinetics: a given dose killing a constant proportion of cells, not a constant number of cells
Cell kill is, therefore, proportional, regardless of tumor burden
A drug with 3 log killing of cancer cells would reduces the tumour burden from 1010 to 107 cells. The same dose used at a tumor burden of 105 cells reduces the tumor mass to 102 cells

9. C C C C C
1012 M
1010 T
108
Number of cells surviving
106
104
102
Time

10. Principles of cancer chemotherapy
The treatment of cancer patients requires a skillful interdigitation of pharmacotherapy with other modalities of treatment (e.g., surgery and irradiation)
In biochemical terms, cancer cells and normal cells are so similar in most respects that it is more difficult to find general, exploitable, biochemical differences between them
Drug therapy is used in patients with cancer to:
Eradicate the disease
Induce a remission
Control symptoms

11. Principles of cancer chemotherapy
Individual patient characteristics determine the choice of modalities
Not all patients can tolerate drugs, and not all drug regimens are appropriate for a given patient
Renal and hepatic function, bone marrow reserve, general performance status, and concurrent medical problems all come into consideration in making a therapeutic plan

12. Benefits of combination therapy
Drugs that act by different mechanisms may have additive or synergistic therapeutic effects
Combination therapy will thus increase log cell kill and diminish the probability of emergence of resistant clones of tumor cells
Several cycles of treatment should be given, since one or two cycles of therapy are rarely sufficient to eradicate a tumor
Most curable tumors require at least six to eight cycles of therapy

13. Benefits of combination therapy
Certain principles have been used in designing such treatments
Efficacy: each drug should have some individual therapeutic activity against the particular tumor being treated
Toxicity: drugs with different dose-limiting toxicities should be used to avoid overlapping toxicities
Optimum scheduling: Intensive intermittent schedules should allow time for recovery from the acute toxic effects, primarily bone marrow toxicity

14. Cell-cycle specificity of drugs
Both normal cells & tumor cells go through growth cycle
Cells from different tumors display differences in the duration of their transit through the cell cycle, and in the fraction of cells in active proliferation

15. Cell-cycle specificity of drugs
Cell cycle specific (CCS) drugs: effective only against replicating cells (most effective against hematological malignancies & in solid tumors in which large proportion of the cells are proliferating)
Cell-cycle nonspecific (CCNS) drugs: many bind to cellular DNA. Useful against low growth and high growth tumors (e.g., carcinomas of the colon or non–small cell lung cancer)

16. Resistance
Primary resistance (inherent drug resistance): melanoma, renal cell cancer, & brain cancer
Acquired resistance: genetic mutation particularly after prolonged administration of suboptimal doses (minimized by short term, intensive, intermittent therapy administration or by drug combinations)

17. Possible mechanisms of Anticancer Drug Resistance
Chemotherapy Agents
Improved proficiency in repair of DNA
Cisplatin, cyclophosphamide, melphalan, mitomycin, mechlorethamine
 In drug activation
Cytarabine, doxorubicin, fluorouracil, mercaptopurine, methotrexate, thioguanine
in drug inactivation
Cytarabine, mercaptopurine
 In cellular uptake of drug
Methotrexate, melphalan
 In efflux of drug (multidrug resistance)
Doxorubicin, daunorubicin, etoposide, vincristine, vinblastine, teniposide, docetaxel, paclitaxel, vinorelbine
Alternative biochemical pathways
Cytarabine, fluorouracil, methotrexate
Alterations in target enzymes (DHFR, topoisomerase II)
Fluorouracil, hyroxyurea, mercaptopurine, methotrexate, thioguanine, teniopside, doxorubicin, daunoruricin, idarubicin

18. Multidrug resistance
It is the major form of resistance to a broad range of structurally unrelated anticancer agents: anthracyclines, vinca alkaloids, taxanes, camptothecins, epipodophyllotoxins
Associated with increased expression of a normal gene (the MDR1 gene) for a cell surface glycoprotein (P-glycoprotein) involved in drug efflux

19. PGP transports drugs out of the cell, which is a process that requires the presence of two ATP-binding domains
Some cytotoxic drugs that are known substrates for PGP include etoposide, daunomycin, taxol, vinblastine and doxorubicin

20. Anticancer Drugs Cytotoxic agents
Alkylating agents and related compounds
Antimetabolites
Cytotoxic antibiotics
Plant derivatives: vinca alkaloids, taxanes, campothecins
2. Targeted therapy
3. Hormones and related compounds

21. Summary of cytotoxic drug action

22. Alkylating agents
Nitrogen mustards: chlorambucil, cyclophosphamide, mechlorethamine
Nitrosureas: carmistine, lomustine
Alkylsulfonates: busulfan
Platinum analogs: cisplatin, carboplatin, and oxaliplatin
Other Alkylating Agents: dacarbazine, procarbazine, & bendamustine

23. Mechanism of actions
Form reactive molecular species/ intermediate that transfer of their alkyl groups to various cellular constituents
The macromolecular sites of alkylation damage include DNA, RNA, proteins, and various enzymes
Alkylations of DNA within the nucleus represent the major interactions that lead to cell death
The major site of alkylation within DNA is the N7 position of guanine

24. Alkylating agents Are cell cycle-nonspecific
Primarily effective against rapidly proliferating cells (late G1 & S phases)
Certain alkylating agents may have damaging effects on tissues with normally low mitotic indices (e.g., liver, kidney, and mature lymphocytes)
Used in combination with other agents to treat a wide variety of lymphatic and solid cancer
Mutagenic & carcinogenic and can lead to secondary malignancies, such as acute leukemia

25. Drug resistance Increase capability to repair DNA lesions
Decrease permeability of the cell to the alkylating agents
Increase production/activity of glutathione of glutathione S-transferase, which can conjugate with and detoxify electrophilic intermediates

26. Cyclophosphamide Activated hepatically 4-hydroxy cyclophosphamide
Clinical uses:
Cyclophosphamide has a wide spectrum of antitumor activity: lymphoma and CLL
Alternative to azathioprine in suppressing immunological rejection of transplant organs
ADR
Hemorrhagic cystitis:
Dysuria and decreased urinary frequency
Due to acrolein in the urine
Can be minimized by vigorous hydration & by use of sodium 2-mercaptoethane sulfonate (MESNA) which “traps” acrolein
Alopecia, NVD, Bone marrow suppression

27. Mechlorethamine It rarely is used in current practice
Severe local reactions of exposed tissues necessitate rapid intravenous injection of mechlorethamine for most clinical uses
The major indication for mechlorethamine is Hodgkin’s disease; the drug is given in the MOPP regimen
MOPP: mechlorethamine, vincristine, procarbazine, and prednisone

28. Mechlorethamine Marked vesicant action (blistering agent)
Reproductive toxicity includes amenorrhea and inhibition of oogenesis and spermatogenesis
Bone marrow suppression
Immunosuppression: herpes zoster infections, especially in patients with lymphomas
Leukopenia
Thrombocytopenia
Alopecia
NVD

29. Ifosfamide Analog of cyclophosphamide
Mainly used for of relapsed germ cell testicular cancer & pediatric and adult sarcomas (1st line)
Has the same toxicity profile as cyclophosphamide. However, it causes greater platelet suppression, neurotoxicity, nephrotoxicity, and in the absence of mesna, urothelial damage

30. Nitrosureas: Carmustine & Lomustine
Are highly lipid-soluble and are able to cross the BBB, making them effective in the treatment of brain tumors
ADEs: bone marrow depression, NV, pulmonary toxicity(cough, dyspnea, and interstitial fibrosis (long term))

31. Platinum analogs: cisplatin, carboplatin, & oxaliplatin
They do not alkylate DNA but instead form covalent metal adducts with DNA inhibiting replication and transcription
They have broad antineoplastic activity
Mainly used for the treatment of ovarian, head and neck, bladder, esophagus, lung, and colon cancers
Cisplatin use is associated with significant nephrotoxicity (30-80%) & hearing loss (10 to 30%)

32. Platinum analogs: cisplatin, carboplatin, & oxaliplatin
Carboplatin: it exhibits significantly less renal toxicity and hearing loss. However, it causes more myelosuppressive than cisplatin
Oxaliplatin: similar to cisplatin and carboplatin, but with significant activity against colorectal cancer. It causes significant neurotoxicity manifested by a peripheral sensory neuropathy
Carboplatin shares cross-resistance with cisplatin in most experimental tumors, while oxaliplatin does not

33. Other alkylating agents
Procarbazine
Temzolomide
Melphalan
Chlorambucil
Busulfan
Bendamustine
Thiotepa
Altretamine

34. Antimetabolites CCS drugs acting primarily in S phase
Are structurally similar to endogenous compounds
These drugs can compete for binding sites on enzymes or can themselves become incorporated into DNA or RNA and thus interfere with cell growth and proliferation
Are also used as immunosuppressants
Folic acid analogues: methotrexate
Purine analogues: mercaptopurine, thioguanine
Pyrimidine analogues: fluorouracil, cytarabine

35. Folate antagonist Methotrexate (MTX)
MXT competitively inhibits the binding of folic acid to the enzyme dihydrofolate reductase (DHFR)
It interfers with the synthesis of tetrahydrofolate (FH4), which serves as the key one-carbon carrier for enzymatic processes involved in de novo synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine
MTX is metabolized to polyglutamte derivatives which are retained in the cell and are also potent inhibitors DHFR
Clearance depends on renal function
Drugs such as aspirin, penicillin, cephalosporins, and NSAIDs inhibit the renal excretion of MTX

36. Anti-metabolites (methotrexate)

37. Folate antagonist Methotrexate (MTX)
Resistance:
Decrease drug transport
Decrease formation of cytotoxic MTX polyglutamates
Increase levels of DHFR
Alter DHFR protein with reduced affinity for MTX
Clinical uses
Cancer: breast cancer, non-Hodgkin's lymphoma, bladder cancer
Immunosuppressive agent in severe rheumatoid arthritis

38. Folate antagonist Methotrexate (MTX)
GIT: NVD, ulcerative mucositis, stomatitis
Melosuppression
Alopecia
Dermatitis
Can be prevented or reveresed by administration of folinic acid (leucovorin) “leucovorin rescue”
Renal damage: Alkalinization of the urine and adequate hydration can help
Hepatotoxicity: cirrhosis (long-term use)
Pulmonary toxicity: cough, dyspnea, fever, & cyanosis
Neurologic toxicities (intrathecal
adminiosrtation): stiff neck, headach, meningeal irritation

39. Leucovorin Folate (Diet) Methotrexate DHFR DHFR FH4 FH2
dTMP
N5, N10- Ch2FH4
dUMP
Purine biosynthesis
Leucovorin

40. Purine analogues
Purine analogues: 6- Mercaptopurine (6-MP) & 6-thioguanine (6-TG)
Are analogs of the natural purines, hypoxanthine (6-MP) and guanine (6-TG)
Are effective in lymphoid malignancies
Analogue of hypoxanthine
Both are inactive and are activated intracellularly by hypoxanthine-guanine phosphoribosyl transferases (HGPRT) to the ribonucleotides 6-thioguanosine-5′-monophosphate (6-thioGMP) & 6-thioinosine-5′-monophosphate (TIMP)
Nucleotides formed from 6-MP and 6-TG inhibit de novo purine synthesis and also become incorporated into nucleic acids

41. Purine analoges
Potential D-D interaction with xanthine oxidase inhibitor (allopurinol): the dose of 6-MP must be reduced by 50–75%
6-TG dose not interact with allopurinol
ADEs: bone marrow supression toxicity & hepatic dysfunction (cholestasis jaundice, necrosis)
Bone marrow suppression is less common with 6-TG

42. Pyrimidine analoges Fluorouracil (5-FU)
5-FU is incorporated into both RNA and DNA:
5-fluoro-2’-deoxyuridine-5’-monophosphate (5-FdUMP): forms a covalently ternary complex with the enzyme thymidylate synthase and the 5,10-methylenetetrahydrofolate
5-fluorouridine-5'-triphosphate (FUTP): incorporate into RNA, where it interferes with RNA processing and mRNA translation
ADEs
Myelosuppression
GIT (mucositis and diarrhea)
Hand-foot syndrome
Neurotoxicity

43. Anti-metabolites (5-Fluorouracil)

44. Pyrimidine analoges Fluorouracil (5-FU)
Clinical uses: Colorectal cancer, anal cancer, breast cancer, gastroesophageal cancer, head and neck cancer, hepatocellular cancer
IV administered b/c of its severe toxicity to the GIT
Resistance:
Depletion of enzymes (especially uridine kinase) that activate 5-fluorouracil to nucleotides
Increased thymidylate synthase level
Altered affinity of thymidylate synthetase for FdUMP
Increase in the pool of the normal metabolite deoxyuridylic acid (dUMP)
Increase in the rate of catabolism of 5-fluorouracil

45. Pyrimidine (cytidine) analoges Capecitabine
Prodrug that is enzymatically converted to 5-FU in the tumor
Adv: orally administered
Clinical use: metastatic breast cancer that is resistant to first line drugs & colorectal cancer
ADEs:
Main: diarrhea and the hand-foot syndrome
Myelosuppression, NV, and mucositis: the incidence is significantly less than that seen with IV 5-FU

46. Pyrimidine analoges 3-Cytarabine (cytosine arabinoside, Ara-C)
It is a CCS (S-phase)
MOA:
Is an analogue of the pyrimidine nucleosides cytidine and deoxycytidine
Is activated by kinases to AraCTP: an inhibitor of DNA polymerases which will incorporate into DNA and can retard chain elongation
This agent has absolutely no activity in solid tumors
Its activity is limited exclusively to hematologic malignancies (e.g. acute myelogenous leukemia and non-Hodgkin's lymphoma)

47. Pyrimidine analoges 3-Cytarabine (cytosine arabinoside, Ara-C)
Resistance
Defect in the transport process
Changes in the kinase enzymes activity
Increased deamination of the drug
Specific Toxicity
Leukoenphalopathy: high doses with intrathecal administration

48. Pyrimidine analoges 4-Gemcitabine
MOA:
Activated to 2',2'-difluorodeoxycytidine triphosphate which will inhibit DNA synthesis by being incorporated into sites in the growing strand that ordinarily would contain cytosine
Resistance:
Alteration in the deoxycytidine kinase
Increase tumor production of endogenous deoxycytidine
Clinical use:
First-line treatment of locally advanced or metastatic adenocarcinoma of the pancreas
Non-small cell lung cancer, bladder cancer, ovarian cancer, soft tissue sarcoma, and non-Hodgkin's lymphoma

50. Folate antagonist Pemetrexed
A new antifolate therapeutic agent that inhibits enzymes within the pyrimidine and purine cycle
It works by inhibiting DHFR & thymidylate synthase
It also inhibits glycinamide ribo-nucleotide formyl transferase (GARFT), an enzyme that is involved in purine synthesis and therefore reduces purine production
Clinical uses: in combination with cisplatin in the treatment of mesothelioma & as first-line treatment of non-small cell lung cancer, as a single agent in the second-line therapy of non-small cell lung cancer
ADEs: myelosuppression, skin rash, mucositis, diarrhea, fatigue, & hand-foot syndrome
Toxicity is reduced by the coadministration of folic acid, vitamin B12 and dexamethasone

51. Sites of Action of Pemetrexed
Sites of Action of Pemetrexed. Actions of pemetrexed on purine and pyrimidine pathways in DNA synthesis. dUMP, Deoxyuridine Monophosphate; TMP, Thymidine Monophosphate; CH2FH2, Methylenetetrahydrofolate; CHOFH4, 10-Formyltetrahydrofolate; FH2, Dihydrofolate; FH4, Tetrahydrofolate; DHFR, Dihydrofolate Reductase; GARFT, Glycinamide Ribonucleotide Formyl Transferase.

52. PLANT ALKALOIDS Vinca alkaloids (vinblastine, vincristine)
These classes differ in their structures and MOA but share the multidrug resistance mechanism, since they are all substrates for the multidrug transporter P- glycoprotein
Cell cycle specific agents
Vinca alkaloids (vinblastine, vincristine)
Podophyllotoxins (etoposide, teniposide)
Camptothecins (Topotecan & Irinotecan)
Taxanes (paclitaxel, docetaxel)

53. A. Vinca alkaloids: Vinblastine, Vincristrine, & vinorelbine
Structurally related compounds derived from Vinca rosea (Vinblastine & vincristrine)
Vinorelbine is a semi-synthetic derivative
Despite their structural similarity, there are significant differences between them in regard to clinical usefulness and toxicity
MOA: The vinca alkaloids bind avidly to tubulin & inhibition tubulin polymerization, which disrupts assembly of microtubules. This inhibitory effect results in mitotic arrest in metaphase (M) prevent, and cell division cannot be completed

55. A. Vinca alkaloids: Vinblastine, Vincristrine, & vinorelbine
Resistance:
Decreased rate of drug uptake
Increased drug efflux : multidrug resistance & cross-resistance usually occurs with anthracyclines, dactinomycin, and podophyllotoxins
ADRs
Vinblastine:
NV, bone marrow suppression, alopecia, & vesicant
Vincristine:
Neurotoxicity: peripheral sensory neuropathy
Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
Vinorelbine:
Bone marrow suppression with neutropenia

56. B. Taxanes: Paclitaxel, Docetaxel, & Ixabepilone
Cell cycle specific (G2/M phase of the cell cycle)
MoA: They bind reversibly to the β-tubulin subunit promoting polymerization and stabilization of the polymer rather than disassembly. Thus, they shift the depolymerization-polymerization process to accumulation of microtubules. The overly stable microtubules formed are nonfunctional, and chromosome desegregation does not occur. This results in death of the cell
Resistance:
Multidrug resistant P-glycoprotein
Mutation in the tubulin structure
Clinical uses: advanced ovarian cancer and metastatic breast cancer. Non-small cell in combination with cisplatin

57. Figure 1 Mechanism of action of docetaxel
Mackler NJ and Pienta KJ (2005) Drug Insight: use of docetaxel in prostate and urothelial cancers. Nat Clin Pract Urol 2: 92–100 doi: /ncpuro0099

58. B. Taxanes: Paclitaxel, Docetaxel, & Ixabepilone
ADEs:
Neutropenia: treatment with colony stimulating factor (Filgrastim) can help
Peripheral neuropathy
Transient, asymptomatic bradycardia: Paclitaxel
Fluid retention: Docetaxel
Serious hypersensitivty: patients are pre-treated with dexamethazone, diphenylhydramine, and an H2 blocker

59. C. podophyllotoxins: Etoposide & Teniposide
Cell cycle specific (most active in the late S to G2 phase of the cell cycle)
MoA: Both drugs bind to the topoisomerase II -DNA complex and prevent resealing of the break that normally follows topoisomerase binding to DNA
The enzyme remains bound to the free end of the broken DNA strand, leading to an accumulation of DNA breaks and cell death
, which results in DNA damage through strand breakage induced by the formation of a ternary complex of drug, DNA, and enzyme

60. Mechanism of action of etoposide

61. D. Camptothecins: Topotecan & Irinotecan
Cell cycle specific (most active in the S phase)
MoA:
Interfere with activity of topoisomerase I, the enzyme responsible for cutting & religating single DNA strands. Inhibition of the enzyme results in DNA damage

62. DNA CPT Topoisomerase I Binding of CPT to topo I and DNA
Action of Type I DNA topoisomerases

63. ANTITUMOR ANTIBIOTICS
Antitumor antibiotics produce their effect mainly by direct action on DNA, leading to disruption of the DNA function
All the anticancer antibiotics now being used in clinical practice are products of various strains of the soil microbe Stremptomyces
Cell cycle non-specific

64. A. Anthracyclin antibiotics
Agents: Doxorubicin, daunorubicin, idarubcin, epirubicin, & mitoxantrone
MoA:
Inhibitoin of topoisomerase II
Intercalation in the DNA: block the synthesis of DNA and RNA, and DNA strand scission
Binding to cellular membranes to alter fluidity and ion transport
Generation of semiquinone free radicals and oxygen free radicals through an iron-dependent, enzyme-mediated reductive process

65. Doxorubicin
Doxorubicin–DNA complex

66. A. Anthracyclin antibiotics
Specific Toxicity:
Cardiotoxicity: arrhythmias and conduction abnormalities, pericarditis, and myocarditis
Results from the generation of free radical and lipid peroxidation
Reduced with:
Lower weekly doses or continuous infusions of doxorubicin
Treatment with the iron-chelating agent dexrazoxane
Liposomal-encapuslated formulations of doxorubicin

67. A. Anthracyclin antibiotics
Radiation recall reaction with erythema and desquamation of the skin observed at sites of prior radiation therapy
Doxorubicin will impart a reddish color to the urine for 1 or 2 days after administration
Bone marrow suppression
Hyperpigmentation of nail beds and skin creases, and conjunctivitis

68. B. Mitomycin (mitomycin C)
It is sometimes classified as an alkylating agent b/c it undergoes metabolic activation through an to generate an alkylating agent that cross-links DNA
ADRs:
Hemolytic-uremic syndrome: microangiopathic hemolytic anemia, thrombocytopenia, and renal failure

69. C. Bleomycin
It is a small peptide that contains a DNA-binding region and an iron-binding domain at opposite ends of the molecule
CCS drug active in G2 phase
MOA:
It acts by binding to DNA, which results in single-strand and double-strand breaks following free radical formation, and inhibition of DNA biosynthesis. The fragmentation of DNA is due to oxidation of a DNA-bleomycin-Fe(II) complex and leads to chromosomal aberrations
Bleomycin is a small peptide that contains a DNA-binding region and an iron-binding domain at opposite ends of the molecule. It acts by binding to DNA, which results in single-strand and double-strand breaks following free radical formation, and inhibition of DNA biosynthesis. The fragmentation of DNA is due to oxidation of a DNA-bleomycin-Fe(II) complex and leads to chromosomal aberrations. Bleomycin is a cell cycle-specific drug that causes accumulation of cells in the G2 phase of the cell cycle. Bleomycin is indicated for the treatment of Hodgkin's and non-Hodgkin's lymphomas, germ cell tumor, head and neck cancer, and squamous cell cancer of the skin, cervix, and vulva. In addition, it can be used as a sclerosing agent for malignant pleural effusions and ascites. One advantage of this agent is that it can be given subcutaneously, intramuscularly, or intravenously (Table 55-4). Peak blood levels of bleomycin after intramuscular injection appear within minutes. Intravenous injection of similar dosages yields higher peak concentrations and a terminal half-life of about 2.5 hours. Elimination of bleomycin is mainly via renal excretion; dose modification is recommended in the setting of renal dysfunction. Pulmonary toxicity is dose-limiting for bleomycin and usually presents as pneumonitis with cough, dyspnea, dry inspiratory crackles on physical examination, and infiltrates on chest x-ray. The incidence of pulmonary toxicity is increased in patients older than 70 years of age, in those who receive cumulative doses greater than 400 units, in those with underlying pulmonary disease, and in those who have received prior mediastinal or chest irradiation. In rare cases, pulmonary toxicity can be fatal. Other toxicities are listed in Table 55-4.

70. C. Bleomycin Specific Toxicity:
Cause: Bleomycin hydrolase, which inactivates bleomycin, virtually absent in lungs and skin
Pulmonary toxicity: pneumonitis with cough, dyspnea, dry inspiratory crackles on physical examination, and infiltrates on chest x-ray
Skin toxicity: hyperpigmentation, erythematosus rashes, and thickening of the skin over the dorsum of the hands and at dermal pressure points, such as the elbows
Bleomycin is a small peptide that contains a DNA-binding region and an iron-binding domain at opposite ends of the molecule. It acts by binding to DNA, which results in single-strand and double-strand breaks following free radical formation, and inhibition of DNA biosynthesis. The fragmentation of DNA is due to oxidation of a DNA-bleomycin-Fe(II) complex and leads to chromosomal aberrations. Bleomycin is a cell cycle-specific drug that causes accumulation of cells in the G2 phase of the cell cycle. Bleomycin is indicated for the treatment of Hodgkin's and non-Hodgkin's lymphomas, germ cell tumor, head and neck cancer, and squamous cell cancer of the skin, cervix, and vulva. In addition, it can be used as a sclerosing agent for malignant pleural effusions and ascites. One advantage of this agent is that it can be given subcutaneously, intramuscularly, or intravenously (Table 55-4). Peak blood levels of bleomycin after intramuscular injection appear within minutes. Intravenous injection of similar dosages yields higher peak concentrations and a terminal half-life of about 2.5 hours. Elimination of bleomycin is mainly via renal excretion; dose modification is recommended in the setting of renal dysfunction. Pulmonary toxicity is dose-limiting for bleomycin and usually presents as pneumonitis with cough, dyspnea, dry inspiratory crackles on physical examination, and infiltrates on chest x-ray. The incidence of pulmonary toxicity is increased in patients older than 70 years of age, in those who receive cumulative doses greater than 400 units, in those with underlying pulmonary disease, and in those who have received prior mediastinal or chest irradiation. In rare cases, pulmonary toxicity can be fatal. Other toxicities are listed in Table 55-4.