ONCOGENES AND ASSOCIATED TUMORS

 1.Growth factor

• PDGF- acts on  PDGF Receptor- Astrocytoma( associated tumor due to mutation)

             mechanism: PDGF binds to PDGF receptor on the astrocytes. Due to mutation, the astrocytes start producing PDGF which again binds to the receptor and the cell grows nd divides continuously. An autocrine loop is formed leading to the tumor formation

                                   

2.Growth factor receptors

• ERBB2[HER2/neu] - Epidermal growth factor receptor- Invasive breast cancers
• RET- neural growth factor receptor- MEN 2A, MEN 2B, Medullary carcinoma of thyroid
• KIT- Stem cell growth factor receptor- GI stromal tumor, testicular seminoma, mast cell diseases, AML

       mechanism: The effect of a single signal is amplified and the cell grows out of control.

                                     

 →HER2/neu overexpression is treated by Trastuzumab

 →When patient has  MEN 2A/2B and has RET mutation, then prophylactically thyroid is removed to avoid medullary carcinoma of thyroid.

3.Signal Transducers

• RAS gene family- GTP binding protein- carcinoma, melanoma, lymphoma                                                                                                                                                                                                           mechanism: Generally, RAS is associated with growth factor receptor in an inactive GDP bound state. when growth factor binds to the receptor, the GDP is replaced by GTP. this complex sends signals to the nucleus which allows cell growth. GTPase activating protein(GAP) will help in conversion of GTP into GDP and stops multiple signals from being passed. Mutated Ras inhibits GAP and multiple signals are sent to the nucleus leading to tumor formation.
•     ABL - Tyrosine kinase - t(9;22) BCR -   CML and some types of ALL.

                                    

4. Nuclear regulators( act on transcription factors)

• c-MYC - Burkitt lymphoma
• N-MYC - Neuroblastoma
• L-MYC - Lung carcinoma                                                                                                                     mechanism: In c-MYC mutation, t(8;14) involving IgH leads to increased production of MYC which will lead to tumor of B cell...Burkitt lymphoma

                                   

5. Cell Cycle Regulators

•  CCND1 - cyclin- Mantle cell lymphoma
• CDK4- cyclin-dependent kinase- Melanoma                                                                                           mechanism: cyclin D/ CDK4 complex phosphorylates the retinoblastoma protein, which promotes progression through the G1/ S checkpoint in cell cycle.     

Mantle zone in the lymph node

                                   

      

AMINOGLYCOSIDE ANTIBIOTICS

Aminoglycosides are bactericidal antibiotics

🠚Aminoglycosides are inactivated under anaerobic conditions. Therefore, anaerobes are resistant to it and facultative anaerobes are more resistant when oxygen supply is deficient . Ex: in big abscesses

🠆These drugs combined with 𝛃-lactams or vancomycin(which affect bacterial cell wall formation) allow the aminoglycosides to penetrate the bacterial cell wall  and exhibit synergism.

MOA

Streptomycin: Binds to 30s ribosomal subunit

other aminoglycosides :Bind to additional sites on 50s subunit and 30s-50s interface

↓

They freeze INITATION process of protein synthesis

↓

Prevent polysome formation & promote their disintegration to non-functional monosomes

↓

Distortion of   mRNA codon recognition 

↓

One or two wrong amino acids are entered in the peptide chain leading to peptides of abnormal lengths are produced

TOXICITIES

1. Ototoxicity: 

Drugs are concentrated in the labyrinthine fluid and slowly removed from it when plasma concentration falls.

a) Cochlear damage:

• No regeneration of the sensory cells occurs, auditory nerve regenerates in retrograde manner
•  Ototoxicity is asymptomatic  and can be detected by audiometry 

b) Vestibular damage 

•  headache first, followed by nausea, vomiting, nystagmus vertigo and ataxia.

2.Nephrotoxicity

Tubular damage resulting in loss of urinary concentrating power, low gfr, nitrogen retention albuminuria and casts.

Important implication of aminoglycosides induced nephrotoxicity is reduced clearance of the antibiotic resulting in higher and more persistent levels in blood which leads to ototoxicity

                                             

3. Neuromuscular blockade

All aminoglycosides reduce Ach release from motor nerve endings.

They interfere with :

• Mobilization of centrally located synaptic vesicles to fuse with terminal membrane.
•  decrease the sensitivity of muscle end plate to Ach.

GENTAMICIN

• Highly active against aerobic gram -ve bacilli ( E.coli, Klebsiella pneumoniae, Enterobacter, H.influenzae, Brucella etc.)
•  gentamicin is ineffective against M.TB and other mycobacteria

Uses

1. Treatment of respiratory infections in immunosuppressed patients, patients in resuscitation wards or on tracheostomy or on ventilator, ICU

• They should not be used for community acquired pneumonias, as they are caused by aerobic gram +ve cocci and anaerobes
• They are used to treat peritonitis

2. Pseudomonas , Klebsiella, Proteus infections: burns, UTI, septicemia

      Topical use for infected burns and for conjunctivitis is permissible

3.Meningitis caused by gram negative bacilli:            3rd generation cephalosporins +                          aminoglycosides                                                          

4. SABE : Gentamicin( 1 mg/kg 8hrly i.m.) combined with penicillin/ ampicillin/ streptomycin

                             

STREPTOMYCIN

• It has narrow anti-bacterial spectrum
• Gram -ve bacilli (Brucella , Yersinia, Francisella , Nocardia, Shigella, Vibrio)

Uses

1.TB- It acts on extracellular bacilli. it penetrates tubular cavities but does not cross CSF.

It is always used in addition to other  1st line anti- TB drugs.

Resistance is developed rapidly when Streptomycin is used alone in TB - most patients have relapse. In case of streptomycin resistant infection, it must be stopped at the earliest because the infection flourishes if the drug is continued due to streptomycin dependence. Non- tubercular mycobacteria is unaffected by streptomycin.

2.Plague- it is rapidly curative in positive patients

3.SABE- Streptomycin+ penicillin/ampicillin/vancomycin

4.Other conditions like UTI, peritonitis, septicemia

Hypersensitivity reactions like rashes, fever exfoliative dermatitis may occur. It has the lowest nephrotoxicity.