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Classification . Alkylating agents. Cyclophosphamide CisplatinProcarbazine BusulfanMechlorethamine . MOA. Alkylating agents. Alkylating Agents- Used in wide variety of hematologic and solid tumors. Thiotepa
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1. Cancer Chemotherapy-2 Dr. R. Senthil Kumar
3. Alkylating agents Cyclophosphamide
Cisplatin
Procarbazine
Busulfan
Mechlorethamine
4. MOA Alkylating agents
5. Alkylating Agents- Used in wide variety of hematologic and solid tumors Thiotepa – ovarian cancer
Busulfan – DOC in CML (***Important ADR-Pulmonary fibrosis).
***Nitrosoureas (Carmustine and lomustine ) - brain tumors
Highly lipid soluble drugs hence reach high concentration in the brain and CSF.
Streptozocin – insulin-secreting islet cell carcinoma of the pancreas
Mechlorethamine – Prodrug. Component of MOPP regimen for Hodgkin’s disease. It is a highly irritant drug so care should be taken to avoid extravasation during IV administration
Chlorambucil (Leukeran): DOC for CLL. Slow acting and least toxic nitrogen mustard. Chlorambucil (Leukeran):
Slow acting and least toxic nitrogen mustard.
Main action is on lymphoid series and produce marked lympholytic effect.
N -non-irritant and usually given orally.
D - drug of choice for chronic lymphatic leukemia (CLL).
Alkyl Sulfonates: Busulphan (Myleran):
Depresses bone marrow with selective action on myeloid series.
DOC for chronic myeloid leukemia (CML).
Common side effects - pigmentation of the skin interstitial pulmonary fibrosis and hyper-uricemia
Nitrosureas ;Carmustine and lomustine
Highly lipid soluble drugs hence reach high concentration in the brain and CSF.
Mainly used in brain tumors and Hodgkin’s diseaseChlorambucil (Leukeran):
Slow acting and least toxic nitrogen mustard.
Main action is on lymphoid series and produce marked lympholytic effect.
N -non-irritant and usually given orally.
D - drug of choice for chronic lymphatic leukemia (CLL).
Alkyl Sulfonates: Busulphan (Myleran):
Depresses bone marrow with selective action on myeloid series.
DOC for chronic myeloid leukemia (CML).
Common side effects - pigmentation of the skin interstitial pulmonary fibrosis and hyper-uricemia
Nitrosureas ;Carmustine and lomustine
Highly lipid soluble drugs hence reach high concentration in the brain and CSF.
Mainly used in brain tumors and Hodgkin’s disease
6. Cyclophosphamide It is a prodrug and is activated by the P-450 enzymes to its active form phosphoramide mustard
The active drug alkylates nucleophilic groups on DNA bases
Particularly at the N-7 position of guanine
This leads to cross linking of bases, abnormal base pairing and DNA strand breakage
8. Cyclophosphamide is a prodrug that must be oxidized by P450 enzymes in the liver to become pharmacologically active. Hydroxylation converts cyclophosphamide to 4-hydroxycyclophosphamide; this active metabolite can be further oxidized to the inactive metabolite 4-ketocyclophosphamide, or undergo ring cleavage to the active metabolite aldophosphamide. Aldophosphamide can be oxidized by aldehyde oxidase to the inactive metabolite carboxyphosphamide or be converted to the highly toxic metabolites acrolein and phosphoramide mustard. Accumulation of acrolein in the bladder can cause hemorrhagic cystitis; this adverse effect of cyclophosphamide can be ameliorated by coadministration of mesna, a sulfhydryl compound that inactivates the acrolein (not shown). Cyclophosphamide is a prodrug that must be oxidized by P450 enzymes in the liver to become pharmacologically active. Hydroxylation converts cyclophosphamide to 4-hydroxycyclophosphamide; this active metabolite can be further oxidized to the inactive metabolite 4-ketocyclophosphamide, or undergo ring cleavage to the active metabolite aldophosphamide. Aldophosphamide can be oxidized by aldehyde oxidase to the inactive metabolite carboxyphosphamide or be converted to the highly toxic metabolites acrolein and phosphoramide mustard. Accumulation of acrolein in the bladder can cause hemorrhagic cystitis; this adverse effect of cyclophosphamide can be ameliorated by coadministration of mesna, a sulfhydryl compound that inactivates the acrolein (not shown).
9. Mechanism of resistance *** The mechanisms mentioned below are common for all the alkylyting agents
Increased DNA repair
Decreased drug permeability
Production of “trapping” agents (thiols)
10. Uses Non-Hodgkin’s lymphoma
Breast Ca
Ovarian Ca
Neuroblastoma
11. ADR Acrolein is the metabolite
Responsible for causing hemorrhagic cystitis
Suprapubic pain
Hematuria
Cyctoscopic findings
***This is prevented/treated by MESNA (mercaptoethanesulfonate)
Rarely cyclophosphamide can cause SIADH and pulmonary toxicity
13. Cisplatin Platinum analog
Same MOA as cyclophosphamide
**Used in testicular carcinoma
Also used for Ca of bladder, lung and ovary
Carboplatin is new drug with better safety profile
ADR
Nephrotoxicity (prevented by Amifostine***)
***Ototoxicity (acoustic nerve damage)
Peripheral neuritis
Severe nausea and vomiting
14. Procarbazine MOA: forms hydrogen peroxide, which generates free radicals that cause DNA damage
Important component of regimens especially for Hodgkin’s lymphoma
ADR
***Disulfiram like reactions
15. Blood in the urine!!! A 30-year-old man is seen at the ER complaining about severe suprapubic pain, fever and signs of passing blood in the urine. He is currently in treatment for non-Hodgkin’s lymphoma (four drug regimen).
What is your preliminary diagnosis?
If it is drug induced, who is “the culprit”?
What is the mechanism behind the latest complication?
How to treat the complication?
Which drug we covered until now has serious nephrotoxic effects?
How to prevent that particular drug induced renal damage?
ADR of:
Procarbazine
Busulfan
17. Antimetabolites They are structurally similar to endogenous compounds
They act as antagonists of:
Folic acid (methotrexate)
Purines (Mercaptopurine and thioguanine)
Pyrimidine (fluorouracil, cytarabine)
18. Antimetabolits: sites of drug action
19. Methotrexate
20. Methotrexate (MTX) MTX is a folic acid analog that binds with high affinity to the active catalytic site of dihydrofolate reductase (DHFR)
Thus it interferes with the synthesis of tetrahydrofolate (THF)
THF 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.
Inhibition of these various metabolic processes thereby interferes with the formation of DNA, RNA, and key cellular proteins. Intracellular formation of polyglutamate metabolites is critically important for the therapeutic action of MTX. MTX polyglutamates are selectively retained within cancer cells, and they display increased inhibitory effects on enzymes involved in de novo purine nucleotide and thymidylate biosynthesis, making them important determinants of MTX's cytotoxic action. Intracellular formation of polyglutamate metabolites is critically important for the therapeutic action of MTX. MTX polyglutamates are selectively retained within cancer cells, and they display increased inhibitory effects on enzymes involved in de novo purine nucleotide and thymidylate biosynthesis, making them important determinants of MTX's cytotoxic action.
22. Contd.. Most commonly used anticancer drug.
Cell cycle specific (CCS) drug and acts during S phase of the cell cycle.
Antineoplastic, immunosuppressant and antiinflammatory
Used in RA, psoriasis
Well absorbed orally; can also be given IM, IV or intrathecally**.
It is bound to plasma proteins, does not cross the BBB and most of the drug is excreted unchanged in urine.
It is a weak acid and so is excreted better at high urine pH. Appropriate hydration and alkalinizing the urine is important to prevent renal tox with MTX
23. ADR Bone marrow suppression (BMS)
Mucositis
Folic acid deficiency
The toxic effects of MTX on normal cells is reduced by administering folinic acid (leucovorin)
This is called leucovorin rescue ****
Higher the dose of MTX more the leucovorin you give**
24. Leucovorin Rescue Mechanism of action of methotrexate and the effect of administration of leucovorin.
FH2 = dihydrofolate
FH4 = tetrahydrofolate
dTMP = deoxythymidine monophosphate
dUMP = deoxyuridine mono phosphate.
25. 6-Mercaptopurine (6-MP) & Thioguanine Both 6-MP and Thioguanine are activated by HGPRT to toxic nucleotides that inhibit several enzymes involved in purine metabolism
***Resistance is due to cancer cells having ?d activity of HGPRT
Cancer cells also ?es alkaline phosphatase that inactivate toxic nucleotides
26. 6-MP & Allopurinol 6-MP is metabolized in the liver by xanthine oxidase and the inactive metabolites are excreted in the urine
***Allopurinol is used frequently to treat/prevent hyperuricemia caused by many anticancer drugs.
If Allopurinol is used with 6-MP then the dose of 6-MP is reduced by more than 75%
Why??
27. Cytarabine (Ara-C) Cytarabine arabinoside is a pyrimidine antimetabolite
The drug is activated by kinases to AraCTP
This acts as an inhibitor of DNA polymerase
***of all antimetabolites, this is the most specific for S phase of tumor cell cycle
It is an important component in acute lukemia regimens
ADR: at high doses cause neurotoxicity (cerebellar dysfunction and peripheral neuritis)
Hand-foot syndrome***
28. 5-FU Mechanism of the cytotoxic action of 5-FU
5-FU is converted to 5-FdUMP, which competes with deoxyuridine monophosphate (dUMP) for the enzyme thymidylate synthetase.
5-FU = 5-fluorouracil
5-FUR = 5-fluorouridine
5-FUMP = 5-fluorouridine monophosphate
5-FUDP = 5-fluorouridine diphosphate
5-FUTP = 5-fluorouridine triphosphate
dUMP = deoxyuridine monophosphate
dTMP = deoxythymidine monophosphate
5-FdUMP = 5-fluorodeoxyuridine monophosphate.
29. Contd.. 5-FU causes, “thymidineless death” of cells
Resistance is due to ?d activation of 5-FU and ?d thymidylate synthase activity
Uses and ADR
Metastatic carcinomas of the breast and the GI tract, hepatoma
Carcinomas of the ovary, cervix, urinary bladder, prostate, pancreas, and oropharyngeal areas
Combined with levamisole for Rx of colon cancer
ADR: nausea, mucositis, diarrhea, ***hand and foot syndrome, Alopecia, hyperpigmentation, neurologic deficits, bone marrow depression Hand-foot syndrome is a side effect of some chemotherapy drugs that results when a small amount of drug leaks out of the blood vessels, damaging tissues. This tends to happen in the hands and the feet because of the increased friction and heat that your extremities are exposed to through daily activities. Symptoms can be prevented by avoiding friction and heat. Treatment consists of reducing or stopping treatment with the drug that caused the syndrome. You may be able to prevent symptoms by avoiding friction or heat.
Symptoms of hand-foot syndrome include:
Tingling or burning
Redness
Flaking
Swelling
Small blisters
Small sores on the palms of the hands or soles of the feet
Hand-foot syndrome is a side effect of some chemotherapy drugs that results when a small amount of drug leaks out of the blood vessels, damaging tissues. This tends to happen in the hands and the feet because of the increased friction and heat that your extremities are exposed to through daily activities. Symptoms can be prevented by avoiding friction and heat. Treatment consists of reducing or stopping treatment with the drug that caused the syndrome. You may be able to prevent symptoms by avoiding friction or heat.
Symptoms of hand-foot syndrome include:
Tingling or burning
Redness
Flaking
Swelling
Small blisters
Small sores on the palms of the hands or soles of the feet
30. Megaloblastic anemia A 50-year-old man is undergoing chemotherapy with a multi-drug regimen after being diagnozed to have a malignant tumor. Soon after the first cycle of chemotherapy, he develops symptoms of severe fatigue and pallor. His Hb is very low and the peripheral smear shows presence of megaloblasts.
What is your prelim. Diagnosis?
Which of the drugs we discussed can be most likely responsible for this complication?
Which compound (and how) administered soon after chemotherapy could have prevented the toxicity?
Which are the anticancer drugs which can cause tingling, feeling of warmth, redness, flaking and blisters (what is this)?
MOA and Mech of resistance to 6-MP and TG?
MOA of 5-FU
32. All derived from plant extractsAll derived from plant extracts
33. Vinka alkaloids (Vinblastine, vincristine) These drugs block the formation of mitotic spindle by preventing the assembly of tubulin dimers into microtubules
***They act primarily on the M phase of cancer cell cycle
Resistance is due to ?d efflux of drugs from tumor cells
34. Vinka alkaloids (animation and ADR) Microtubule Synthesis animation
Inhibition of spindle function
ADR
Severe neurotoxicity
Paresthesias
Loss of reflexes
Foot drop
Ataxia
35. ABVD regimen:
• Adriamycin (generic name Doxorubicin) • Bleomycin (common brand name: blenoxane)• Vinblastine (common brand names: velban, velsar, velbe) • Dacarbazine (common brand name: DTIC, DTIC-Dome)
MOPP regimen
• Mustargen (generic name mechlorethamine, MSD, mustine or nitrogen mustard) • Vincristine (also called Oncovin or VCR) • Procarbazine (also called Matulane or possibly Natulan)• Prednisone (sometimes called Deltasone or Orasone)ABVD regimen:
36. Etoposide & Teniposide Acts by inhibiting topoisomerase II
These drugs are most active in late S and early G2 phase
Used in combination Tx of small cell carcinoma of lung, prostrate and testicular carcinomas
Other topoisomerase inhibitors:
Topotecan, Irinotecan
Both act by inhibiting topoisomerase-I
37. Topoisomerase inhibitors
38. Paclitaxel & Docetaxel These drugs act by interfering with mitotic spindle
They prevent micotubule disassembly into tubulin monomers
Taxanes animation
ADR
Neutropenia
Peripheral neuropathy
39. Questions What is the diff between MOA of taxanes and Vinca alkaloids
Which is the marrow sparing anticancer drug
Topoisomerase-1 inhibitors
Topoisomerase-2 inhibitors
40. Anticancer Antibiotics Anthracyclines:
Doxorubicin (Adriamycin)
Daunorubicin
Bleomysin
Dactinomycin
Mitomycin
41. Doxorubicin & Daunorubicin These drugs intercalate between base pairs, inhibit topoisomerase II and also generate free radicals
They block RNA and DNA synthesis and cause strand scission
*These are CCNS drugs
Used as a component in ABVD regimen in Hodgkin’s lymphoma ABVD regimen
• Adriamycin (generic name Doxorubicin) • Bleomycin (common brand name: blenoxane)• Vinblastine (common brand names: velban, velsar, velbe) • Dacarbazine (common brand name: DTIC, DTIC-Dome)ABVD regimen
42. ADR Cardiac toxicity (due to generation of free radicals)
Acute form: arrthythmias, ECG changes, pericarditis, myocarditis
Chronic form: ***Dilated cardiomyopathy, heart failure
****Rx with dexrazoxane
This is an inhibitor of iron mediated free radical generation
Bone marrow depression, Total alopecia
Radiation recall reaction
43. Bleomycin Acts through binding to DNA, which results in single and double strand breaks following free radical formation and inhibition of DNA synthesis
The DNA fragmentation is due to oxidation of a DNA-bleomycin-Fe(II) complex and leads to chromosomal aberrations
CCS drug that causes accumulation of cells in G2
Uses
ABVD regimen for Hodgkin’s
Intracavitary therapy in ovarian and breast cancers (Sclerosing agent)
ADR
***Pulmonary fibrosis
44. Questions ADR of anthracyclines? (clinical symptoms)
Why ADR with anthracyclines?
How to treat it?
ADR of bleomycin?
45. Hormonal agents Glucocorticoids
Sex hormone antagonists
GnRH analogs
Aromatase inhibitors
46. Glucocorticoids (Prednisone) Because of their marked lympholytic action, they are used in acute leukemias and lymphomas.
Have anti-inflammatory effect
Increase appetite
Produce euphoria (feeling of well being)
Increase body weight
Suppress hypersensitivity reaction due to certain anticancer drugs
Control hypercalcemia
Control bleeding
Have non-specific antipyretic effect
Increase the antiemetic effect of ondansetron/granisetron/ metoclopramide
47. Sex hormone antagonists
48. Tamoxifen It is a SERM
Blocks the binding of estrogen to receptors of estrogen sensitive cancer cells in bresat tissue
It is used in receptor positive breast carcinoma
Also useful in progestin resistant endometrial carcinoma
ADR:
Hot flushes, vaginal bleeding and venous thrombosis
Other drugs
Flutamide: androgen receptor antagonist used in prostatic carconima
ADR for flutamide includes: gynecomastia, hot flushes
49. MOA of drugs
50. GnRH analogs Leuprolide, gosarelin and naferelin
Effective in management of Prostatic carcinomas
When given in constant doses they inhibit release of pituitary LH and FSH
These drugs suppress gonadal function due to down regulation and desensitization of Gn-RH receptors
ADR
Leuprolide may cause gynecomastia, hematuria, impotence and testicular atrophy Gonadotropin-releasing hormone is normally secreted by the hypothalamus and stimulates the anterior pituitary to secrete the gonadotropic hormones, luteinizing hormone (LH; the primary stimulus for the secretion of testosterone by the testes), and follicle-stimulating hormone (FSH; which stimulates the secretion of estrogen). The synthetic nonapeptides, leuprolide [loo-PROE-lide] and goserelin [GOE-se-rel-in], are analogs of GnRH. As GnRH agonists, they occupy the GnRH receptor in the pituitary, which leads to its desensitization and, consequently, inhibition of release of FSH and LH. Thus, both androgen and estrogen syntheses are reduced. Response to leuprolide in prostatic cancer is equivalent to that of orchiectomy (surgical removal of one or both testes), with regression of tumor and relief of bone pain. Gonadotropin-releasing hormone is normally secreted by the hypothalamus and stimulates the anterior pituitary to secrete the gonadotropic hormones, luteinizing hormone (LH; the primary stimulus for the secretion of testosterone by the testes), and follicle-stimulating hormone (FSH; which stimulates the secretion of estrogen). The synthetic nonapeptides, leuprolide [loo-PROE-lide] and goserelin [GOE-se-rel-in], are analogs of GnRH. As GnRH agonists, they occupy the GnRH receptor in the pituitary, which leads to its desensitization and, consequently, inhibition of release of FSH and LH. Thus, both androgen and estrogen syntheses are reduced. Response to leuprolide in prostatic cancer is equivalent to that of orchiectomy (surgical removal of one or both testes), with regression of tumor and relief of bone pain.
51. Aromatase inhibitors The aromatase reaction is responsible for the extra-adrenal synthesis of estrogen from androstenedione
This takes place in liver, fat, muscle, skin, and breast tissue, including breast malignancies.
Peripheral aromatization is an important source of estrogen in postmenopausal women.
Aromatase inhibitors decrease the production of estrogen in these women.
52. Contd..
53. Contd.. Anastrozole and Letrozole
These drugs inhibit the aromatase enzyme
****Used in Tx of postmenopausal women with metastatic breast ca (1st line drug)
ADR includes: bone pain and peripheral edema
54. Miscellaneous agents Asparaginase, imatinib, interferons, monoclonal antibodies
55. Asparaginase L-Asparaginase catalyzes the deamination of asparagine to aspartic acid and ammonia.
L-Asparaginase is used in combination therapy to treat childhood acute lymphocytic leukemia
Its mechanism of action is based on the fact that some neoplastic cells require an external source of asparagine because of their limited capacity to synthesize sufficient amounts of that amino acid to support growth and function.
L-Asparaginase hydrolyzes blood asparagine and, thus, deprives the tumor cells of this amino acid, which is needed for protein synthesis
ADR
Acute pancreatitis*****
56. Contd..
57. Imatinib Example of a drug, whose development was guided by knowledge of a specific oncogene
Used for the treatment of chronic myeloid leukemia
Acts by inhibiting tyrosine kinase activity of the protein product of the Bcr-Abl oncogene
This gene is expressed in CML
58. MOA of imatinib Imatinib MOA
59. Interferons Human interferons have been classified into three types—a, ß, and ?—on the basis of their antigenicity.
The a interferons are primarily leukocytic, whereas the ß and ? interferons are produced by connective tissue fibroblasts and T lymphocytes, respectively.
Recombinant DNA techniques in bacteria have made it possible to produce two species designated interferon-a-2a and -2b used in Tx of neoplastic diseases.
***Interferon-a-2a is presently approved for the management of hairy-cell leukemia, chronic myeloid leukemia, and acquired immunodeficiency syndrome (AIDS)–related Kaposi sarcoma.
***Interferon-a-2b is approved for the treatment of hairy-cell leukemia, melanoma, AIDS-related Kaposi's sarcoma, and follicular lymphoma.
60. Monoclonal Antibodies They are created from B lymphocytes (from immunized mice or hamsters) fused with “immortal” B-lymphocyte tumor cells.
The resulting hybrid cells can be individually cloned, and each clone will produce antibodies directed against a single antigen type.
Recombinant technology has led to the creation of “humanized” antibodies that overcome the immunologic problems previously observed following administration of mouse (murine) antibodies.
Currently, several monoclonal antibodies are available in the United States for the treatment of cancer.
Trastuzumab, rituximab, bevacizumab, and cetuximab
61. Trastuzumab In patients with metastatic breast cancer, overexpression of transmembrane human epidermal growth factor–receptor protein 2 (HER2) is seen in 25 to 30 % of patients.
Trastuzumab is a recombinant DNA–produced, humanized monoclonal antibody, specifically targets the extracellular domain of the HER2 growth receptor that has intrinsic tyrosine kinase activity.
Trastuzumab binds to HER2 sites in breast cancer tissue and inhibits the proliferation of cells that overexpress the HER2 protein, thereby decreasing the number of cells in the S phase.
62. FDA approved MAb
63. Questions??? What are Flutamide and Leuprolide and mention their uses?
MOA of tamoxifen?
MOA of anastrozole and letrozole?
Important clinical indication for these drugs?
Important ADR of L-asparaginase?
Clinical symptoms of ADR (including lab)
MOA and use of imatinib?
MABs used in cancer chemotherapy (know four of them circled above)
64. Treatment of Specific cancers Hodgkin’s disease:
ABVD regimen (doxorubicin,bleomycin,vinblastine,dacarbazine)
MOPP regimen (mechorethamine,vincristine,procarbazine,prednisone)
NHL: CHOP regimen (cyclophosphamide,doxorubicin,vincristine,prednisone)
Multiple myeloma : MP protocol (melphalan and prednisone)
Breast ca:
CMF protocol (cyclophosphamide-MTX-fluorouracil)
Tamoxifen
Anastrozole, letrozole
65. Prevention/management of Cancer Chemotherapy induced ADR Nausea and vomiting : 5-Ht3 antagonist (ondansetron)
Bone marrow suppression : Filgrastim, Sargromastim (colony stimulating factors)
MTX toxicity : Leucovorin
Cyclophosphamide toxicity : MESNA
Cisplatin toxicity : Amifostine
Anthracycline toxicity ; Dexaroxazone