Antineoplastic drugs-alkylating agents

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Antineoplastic drugs-Alkylating agents : 

Antineoplastic drugs-Alkylating agents DR.NATASHA

INTRODUCTION : 

INTRODUCTION uncontrolled multiplication and spread of abnormal forms of the body's own cells one of the major causes of death in the developed nations cancer is largely a disease of later life, and with advances in public health and medical science many more people now live to an age where they are more liable to contract cancer

Historical perspective : 

Historical perspective Before advent of microscope-collection of mucus /noncellular matter Otto warburg-cancer theory of combustion Viral theory-1970 retroviral oncogenes Familial cancer studies-tumour suppressor genes Birth of cancer genetics

aetiology of cancer : 

aetiology of cancer Genetic Oncogenes-ATK1 gastric cancer Tumour suppressor genes-p53,Rb Caretaker genes(integrity of genome) Epigenetic- hormonal Environmental toxins Virus-EBV causing burkitts lymphoma

Genesis of a cancer cell : 

Genesis of a cancer cell

Slide 7: 

Cancer cells- uncontrolled proliferation dedifferentiation and loss of function invasiveness metastasis benign and malignant tumors

Slide 8: 

There are three main approaches to treating established cancer- surgical excision irradiation Chemotherapy Biological therapy(immunotherapy/gene therapy)

PRINCIPLES OF CANCER CHEMOTHERAPY : 

PRINCIPLES OF CANCER CHEMOTHERAPY Combination of agents-overcome the log kill of individual drugs(skipper and schabel’s log kill hypothesis) Tumour growth not constant and peaks when the tumour is 1/3rd its maximum size-gompertzian curve Sanctuary sites-CNS requiring adjuvant radiation/intrathecal administration of drugs

Chemotherapy regimens : 

Chemotherapy regimens Hodgkin's lymphoma- (ABVD) Doxorubicin, bleomycin, vinblastine,dacarbazine Non-Hodgkin's lymphoma (CHOP) Cyclophosphamide, hydroxy-doxorubicin, vincristine, prednisolone Breast -CMF Cyclophosphamide, methotrexate, 5-fluorouracil

Slide 12: 

Chemotherapy-curative or palliative Curative-ALL/AML/Hodgkins disease Palliative-CML/CLL/bladder carcinoma Neoadjuvant chemotherapy-preoperative shrink the tumour size Adjuvant chemotherapy-post operative eg breast carcinoma Multimodal therapy-surgery/chemotherapy/radiotherapy

DOSING schedule : 

DOSING schedule Dose dense chemotherapy- standard doses given frequently along with growth factor support Smaller doses given weekly(metronomic dosing) Animal studies have shown reduction in drug resistance

Slide 14: 

Although most anticancer drugs are used systemically, there are selected indications for local or regional administration intraperitoneal therapy for ovarian cancer hepatic artery infusion+/- embolization-hepatocellular carcinoma Intravesical- bladder cancer

Evaluation of chemotherapeutic response : 

Evaluation of chemotherapeutic response Subjective-relief from pain,dyspnea Objective- complete response, which is a complete disappearance of all detectable disease clinically and radiologically (CR) partial response, which is conventionally defined as more than a 50% reduction in the size of the tumour(PR)

Drug resistance : 

Drug resistance Primary resistance-malignant melanonma,brain tumours Acquired resistance Single agent resistance-genetic mutation MDR-expression of p-Glycoprotein involved in drug efflux Overexpression of MRP 1-multiple drug resistant protein Upregulation of bcl 2 ,bax

Slide 17: 

Cancer cells have uncontrolled proliferation because of changes in: growth factors and/or their receptors intracellular signalling pathways, particularly those controlling the cell cycle and apoptosis telomerase expression tumour-related angiogenesis.

Slide 18: 

Most current anticancer drugs, particularly those that are 'cytotoxic', affect only one characteristic aspect of cancer cell biology-cell division antiproliferative action results from an action during S phase of the cell cycle, and the resultant damage to DNA initiates apoptosis narrow therapeutic window between effective treatment of the cancer and normal tissue toxicity

Common toxic effects : 

Common toxic effects Bone marrow toxicity (myelosuppression) Nausea and vomitting loss of hair (alopecia) mucositis GI mucosal haemorrhages,ulceration Fatigue Lymphocytopenia-CMI and HI Teratogenic

Drug specific toxicity : 

Drug specific toxicity Cardiotoxicity- anthracyclines Pulmonary toxicity- bleomycin Neurotoxicity- cisplatinum, vinca alkaloids, taxanes Nephrotoxicity- cisplatinum Skin plantar-palmar dermatitis- 5-FU Sterility- alkylating agents Secondary malignancy- alkylating agents, epipodophyllotoxins

Cell cycle : 

Cell cycle

Mechanism and site of action : 

Mechanism and site of action

Alkylating agents : 

Alkylating agents alkylating agents are compounds that are capable of introducing alkyl groups into nucleophilic sites on other molecules through the formation of covalent bonds. nucleophilic targets for alkylation include the sulfhydryl, amino, phosphate, hydroxyl, carboxyl, and imidazole groups

Slide 28: 

The macromolecular sites of alkylation damage include DNA, RNA, and various enzymes the degree of DNA alkylation correlates especially well with the cytotoxicity of these drugs accounts for the mutagenic and carcinogenic properties of the alkylating agents

Slide 29: 

7-nitrogen (N7) and 6-oxygen (O6) of guanine have been shown to be particularly susceptible to attack by electrophilic compounds

Slide 30: 

1. Cross-linkage. Bifunctional alkylating agents such as the nitrogen mustards, may form covalent bonds with each of two adjacent guanine residues. Such interstrand cross-linkages will inhibit DNA replication and transcription. Intrastrand cross-links also may be produced between DNA and a nearby protein.

Slide 31: 

2. Mispairing of bases. Alkylating at N7 changes the O6 of guanine to its enol tautomer, which can then form base pairs with thymine. This may lead to gene miscoding, with adenine– thymine pairs replacing guanine–cytosine. The result is the production of defective proteins.

Slide 32: 

3. Depurination. N7 alkylation may cause cleavage of the imidazole ring and excision of the guanine residue, leading to DNA strand breakage.

Slide 33: 

intramolecular cyclization ethyleneimonium ion that may directly or through formation of a carbonium ion transfer an alkyl group to a cellular constituent

SAR : 

Nitrogen mustards-2choroethyl group Modification of this group changes stability,reactivity, lipopilicity SAR

Activation of agent by host metabolism : 

Activation of agent by host metabolism

Slide 36: 

Cyclophosphamide-CYP2B6 Ifosfamide-CYP3A4 Slower activation of ifosfamide Greater production of chloracetaldehyde(toxic) Dacarbazine-N-demethylation MTIC mehyl diazonium ion

Slide 37: 

Temozolomide-spontaneous nonenzymatic activation to form MTIC Nitrosoureas-spontaneous breakdown into an alkylating intermediate-2 chloroethyl diazonium ion

Slide 38: 

Stable ethyleneiminium derivatives Hexamethylamine-structural similarity to TEM

Slide 39: 

Alkylation of DNA is through formation of methyl radicals

Uptake : 

Uptake Unknown mechanism Melphelan/mechlorethamine-active transport Nitrosoureas-passive diffusion due to high lipophilicity

Pharmacological action : 

Pharmacological action Recognition of adduct creation of DNA strand breaks Intact apoptotic response P53 G1-S phase INTACT DNA REPAIR SYSTEMS

Bifunctional alkylating agents Vs monofunctional methylating agents : 

Bifunctional alkylating agents Vs monofunctional methylating agents Methylation(procarbazine,temozolamide) Frequently bypassed by DNA repair mechanisms Carcinogenicity/mutagenicity

Mechanism of resistance to alkylating agents : 

Mechanism of resistance to alkylating agents Decreased permeation of actively transported drugs(mechlorethamine) Thiols which detoxify electrophilic intermediates Increase activity of DNA repair mechanism Increased rates of metabolism of activated forms of cyclo/ifosfamide to their inactive metabolites by aldehyde dehydrogenase

Toxicities of alkylating agents : 

Toxicities of alkylating agents Bone marrow Mucosal Neurotoxicity Other organ toxicity leukemogenesis

Bone marrow toxicity : 

Bone marrow toxicity Dose limiting Myelosuppression acute (6-10 days) delayed(4-6 weeks) Nitrogen mustard,melphelan,chlorambucil,ifosfamide Busulfan,carmustine Least BM toxicity-cyclophosphamide cellular and humoral immunity

Mucosal toxicity : 

Mucosal toxicity Actively dividing cells Ulceration,intestinal denudation High dose chemotherapy Lesser mucosal damage-cyclophosphamide melphelan thiotepa

neurotoxicity : 

neurotoxicity CNS-nausea and vomitting MC agents-iv nitrogen mustard/carmustine Ifosfamide-altered MS Coma siezures chloracetaldehyde cerebellar ataxia High dose busulfan-siezures,increases clearance of phenytoin

Other organ toxicities : 

Other organ toxicities High dose and prolonged use Irreversible and lethal sometimes Common to all-pulmonary fibrosis sterility Busulfan/carmustine-VOD of liver Nitrosoureas/ifosfamide-renal failure Cyclo/ifosfamide-haemmorhagic cysttis -RTA in children aged <5 yrs

Slide 49: 

Mechlorethamine/nitrosoureas- strong vesicant Damage to vein on repeated use Ulceration on extravasation

leukemogenesis : 

leukemogenesis Highly leukemogenic class Acute nonlymphocytic leukemia 4% incidence after therapy for 4-5 years Associated with chr 5,7 deletions Myelodysplastic BM picture MC-melphelan/procarbazine/nitrosoureas Least toxic-cyclophosphamide

High dose chemotherapy : 

High dose chemotherapy Most anticancer drugs have a sigmoid dose-response relationship Higher dose greater response/toxicity Toxicity limiting dose-bone marrow failure Restoration-Infusion of stem cells Haematopoietic stem cell transplant Autologous allogenic

Nitrogen mustards : 

Nitrogen mustards Mechlorethamine Cyclophosphamide Ifosfamide Chlorambucil melphelan

history : 

history 1940’s –WWI and WWII Goodman and Gillman-hired by dept of defense to study the effect of nitrogen mustard on cancer cells

mechlorethamine : 

mechlorethamine a derivative of the war gas sulfur mustard first modern anticancer drug Rapid iv dose to prevent local reaction(strong vesicant) T ½-10 min Toxicity-myelosuppresion ,nausea and vomitting,alopecia,teratogenic,carcinogenic in animals Local reaction-tender brawny edema treated with injection of isotonic sodium thiosulfate

Therapeutic use : 

Therapeutic use MOPP regimen-Hodgkins disease IV bolus dose 6 mg/m2 on day 1 and 8 of the 28 day cycle Presently cyclophosphamide,melphelan have replaced it Topical application-cutaneous T cell lymphoma

cyclophosphamide : 

cyclophosphamide most versatile and useful of the nitrogen mustards favorable therapeutic index and the broadest spectrum of antitumor activity Metabolised by CYP2B6 phosphoramide mustard acrolein Antitumour activity toxic to bladder

Slide 57: 

oral, im, iv dosage forms T ½-6.5 hrs Eliminated by kidney

toxicity : 

toxicity Acrolein induced haemorrhagic cystitis Treatment with MESNA Adequate hydration during therapy Discontinue on brisk haematuria Refractory bladder haemorrhage-cystectomy to control bleeding SIADH-at doses >50 mg/kg ,can cause water intoxication High dose-pulmonary,renal,cardiac,hepatic toxicity

Therapeutic use : 

Therapeutic use Adjuvant therapy-breast /lymphoma/CLL Single agent-100 mg/m2 IV x 14 days Combination -500 mg/m2 IV x 14 days CMF regimen-along with MTX,5-FU CVP/COP regimen-lymphoma High dose chemotherapy with stem cell rescue dose-5-7 gm/m2 x 5 days Curative in burkitts lymphoma

Slide 60: 

Ovarian cancer Oat cell cancer lung Non hodgkins lymphoma To prevent organ rejection Non- neoplastic disorder- wegeners granulomatosis Rheumatoid arthritis Nephrotic syndrome

ifosfamide : 

ifosfamide analogue of cyclophosphamide metabolic activation to form 4-hydroxyifosfamide metabolism, serum half-life,and excretion of ifosfamide are similar to those of cyclophosphamide germ cell cancers of the testis, lymphomas, sarcomas, and carcinomas of the lung, breast, and ovary

Therapeutic use : 

Therapeutic use Approved in combination for germ cell testicular cancer and sarcomas High dose chemotherapy- Hallucinaton Siezure coma less myelosuppressive than cyclophosphamide but is more toxic to the bladder

melphelan : 

melphelan amino acid derivative of mechlorethamine bioavailability of the oral preparation is quite variable (25–90%) T ½-45-90 min Toxicity-bone marrow suppression tends to be more prolonged and affects both white cells and platelets

Therapeutic use : 

Therapeutic use Palliative therapy in multiple myeloma Oral 6-8 mg/d x 4 days followed by a 4wk rest period IV dose-15 mg/m2 over 20 min Breast/ovarian cancer

chlorambucil : 

chlorambucil aromatic nitrogen mustard intermediate in chemical reactivity between mechlorethamine and melphalan Oral absorption adequate T ½-1.5 hrs Bone marrow toxicity Carcinogenic??AML

Therapeutic uses : 

Therapeutic uses CLL-0.1-0.2 mg/kg od x 3-6 wks Waldenstroms macroglobulinemia Myeloma Other lymphomas

nitrosoureas : 

nitrosoureas non-cross-resistant with other alkylating agents biotransformation, occurs by nonenzymatic decomposition-alkylating and carbamoylating activities highly lipid-soluble cross BBB Treatment of brain tumours/lymphoma Carmustine (BCNU) lomustine (CCNU) semustine (methyl-CCNU)

Carmustine (BCNU) : 

Carmustine (BCNU) alkylation of DNA at the O 6-guanine position Methylation of the AGT promoter region inhibits its expression in about 30% of primary gliomas t ½ 15 -90 mins Concentration of active metabolites 15-30% of the plasma values Toxicity-hepatic veno-occlusive disease, pulmonary fibrosis, renal failure, and secondary leukemia

Therapeutic use : 

Therapeutic use intravenously at doses of 150 to 200 mg/m2, given by infusion over 1 to 2 hours and repeated at 6 weeks. carmustine is used with procarbazine in the treatment of malignant gliomas implantable carmustine wafer (GLIADEL)-high grade malignant glioma/gliobastoma multiforme

Slide 70: 

semustine (methyl-CCNU)- renal failure Streptozocin-antibiotic has a methylnitrosourea (MNU) moiety attached to the 2 carbon of glucose Experimental induced diabetes in animal models Use-human pancreatic islet cell carcinoma and malignant carcinoid tumors Iv 500 mg/m2 once daily for 5 days x 6 weeks

Slide 71: 

Toxicity- Does not cause profound myelosuppression 20% Mild, reversible renal or hepatic toxicity -2/3rds Streptozocin should not be given with other nephrotoxic drugs

Alkyl Sulfonates : 

Alkyl Sulfonates Busulfan (Myleran) is a bifunctional methanesulfonic ester Oral/IV At usual therapeutic dosages, busulfan is selectively toxic to granulocyte precursors rather than lymphocytes

Therapeutic use : 

Therapeutic use CML-2 to 8 mg for adults (~60 ug/kg or 1.8 mg/m2 for children) aim of reduction of the TLC - 10,000 cells/mm3 A normal leukocyte count usually is achieved within 12 to 20 weeks Daily maintenance doses are 1 to 3 mg High dose busulfan and cyclophosphamide-preparation of leukemia patients for bone marrow transplant

Slide 74: 

High-dose busulfan - veno-occlusive disease of the liver in up to 10% of patients seizures, hemorrhagic cystitis, permanent alopecia, and cataracts Busulfan induces phenytoin clearance-use of lorazepam to prevent seizures

Ethylenimines and Methylmelamines : 

Ethylenimines and Methylmelamines Altretamine formerly known as hexamethylmelamine (HEMA) palliative treatment for persistent or recurrent ovarian cancer following treatment failure with a cisplatin- or alkylating agent-based combination Oral formulation only myelosuppression and neurotoxicity

Slide 76: 

Thiotepa three ethyleneimine groups stabilized by attachment to the nucleophilic thiophosphoryl base triethylenephosphoramide (TEPA) active metabolite Its current use is primarily for high-dose chemotherapy regimens

Slide 77: 

conventional doses (up to 80 mg/m2) high-dose therapy of 300 mg/m2 per day x 5 days Toxicity-myelosuppression/mucositis High doses-coma,siezures

Triazenes : 

Triazenes Dacarbazine(DTIC) functions as a methylating agent after metabolic activation in the liver monomethyl triazeno metabolite, MTIC is cytotoxic Use-melanoma, Hodgkin's disease, and soft tissue sarcomas Toxicity-nausea and vomitting,myelosuppression,flu like syndrome

Slide 79: 

Temozolomide Standard agent used in combination with radiation for malignant glioma Oral BA-100%

Methylhydrazines : 

Methylhydrazines Procarbazine –synthesized in search of monoamine inhibitors Oxidative metabolism generates azoprocarbazine and H2O2, which may be responsible for DNA strand scission Combination regimens Hodgkin's disease -MOPP Non-Hodgkin's lymphoma Brain tumors-PCV(lomustine/vincristine)

Toxic effects : 

Toxic effects Leukopenia/thrombocytopenia Neurological/dermatological-5-10% Additive sedative effect with CNS depressants Disulfiram reaction Carcinogenic-5-10% risk of acute leukemia Mutagenic Teratogenic