Chap 55: Cancer chemotherapy

CELL CYCLE KINETICS
Introduction
- tumor stem cells

• subpopulation within tumor cells
• has ability to proliferate repeatedly --> hence metastasis
• chemotherapy agents aimed at targeting tumor stem cells
• by definition non-TSC is sterile (they are irreversibly differentiated) ie not target of ctx

- cell cycle specific (CCS) drugs

• effective against proliferating cells - G1 - hematological malig
• solid tumors with predominantly rapidly dividing/in growth faction

- cell cycle non-specific (CCNS) drugs

• many binds to DNA or damage microtubule good for both proliferating and non-proliferating cells - G1 and G0 (resting stage)
• but G1 stage cells would be more sensitive

Resistance to cytotoxics
- primary resistance

• no response on 1st exposure
• due to genomic instability
• brain ca, RCC, melanoma

- acquired resistance

• mutation in chemosensitive tumor cells
• expression of normal gene - MDR1 gene
• expression of abnormal gene - multidrug resistance protein 1 (MRP1) gene

POLYFUNCTIONAL ALKYLATING AGENTS
- bisamines, cyclophosphamide, mechlorethamine, melphalan, chlorambucil
- MOA

• transfer alkyl groups to varius cellular components --> likely DNA --> cell death (N7 position of guanine in DNA)
• cells most susceptible to alkylation at G1

- Resistance

• increased cell ability to repair DNA lesion, reduced permeability, increase gluthathione (inactivates alkylating agent)
• resistance to 1 alkylating agent = all generally

- SE

• direct vesicant efx - at site of injection (into peripheral v is ok - diluted immediated)
• systemic toxicity - affects fast growing tissues (bone marrow, GIT, reporudctive system)
• emetogenic - mediated by 5HT - use 5HT antagonist (ondansetron)

Related drugs acting as alkylating agents
- procarbazine

• oral agent
• use: Hodgkin's, NHL, brain tumors
• leukemogenic, teratogenic, mutagenic --> increased risk of 2ary cancer

- dacarbazine

• melanoma, HD, soft tissue sarcome

- altretamine
- cisplatin

• inorganic metal complex - discovered serendipitously that Pl inhibit division and induce filamentous growth of E coli
• exact mechanism unknown but likely alkylating agent
• solid tumors - small cell/NSCLC/oesophageal/gastric/H+Neck/GU - testicular, ovarian, bladder
• + bleomycin/etoposide --> cure nonseminomatous testicular ca
• nephrotoxic --> needs hydration

- carboplatin

• 2nd generation platinum analogue --> same spectrum of solid tumors
• toxicity --> myelosuppression, significantly less renal toxicity + GI toxicity than cisplatin
• don't need IV hydration --> widely replaced cisplatin

- oxaliplatin

• 3rd generation platinum
• MOA same
• used for tumors resistant to carbo + cis
• FOLFOX (5-FU, leucovorin) - advanced colorectal ca
• neurotoxic --> dose-limiting, peripheral sensory neuropathy (reversible)

ANTIMETABOLITES
- tumors has some quantitative differences in metabolism from norm cells
- inhibit nucleotide and nucleic acid synthesis
- methotrexate

• antifolate - binds to dihydrofolate reductase --> DNA inhibition
• toxicity - not metabolised, hence toxicity = dose administered
• efx of MTX reversed by leucovorin (5-formyltetrahydrofolate)

- premetrexed

• antifolate like MTX
• + cisplatin for mesothelioma/single agent in NSCLC
• myelosuppression, skin rash, mucositis, diarrhoea, fatigue

PURINE ANTAGONIST
- 6-MP and 6-TG

PYRIMIDINE ANTAGONIST
- 5-FU
- capecitabine
- cytarabine
- gemcitabine

CLINICAL PHARMACOLOGY FOR CHEMOTHERAPY
Introduction
- depends on

• growth fraction
• spontaneous cell death rate
• most cell in G0?
• hypoxic stem cells?
• cell cycle specific?
• hormonal control?
• drug metabolised by liver (cyclophosphamide) or tumor (capecitabine)?

- generally given in 3-4 wk pulse therapy - reason for norm cells to repair itself but not tumor - complete hematologic and immunologic recovery btw courses

The Leukemias
- acute childhood - good px
- acute adult
- chronic myeloid leukemia
- chronic

Breast cancer
- radiotherapy
- chemo
- hormonal - herceptin (trastuzumab) for HER-2 receptor +ve pt

Lung cancer
- NSCLC (majority - 75-80%) vs SCLC
- NSCLC - if advanced - bad px, best rx is avoid smoking + early detection
- SCLC - responds excellently to platinum

Testicular cancer
- platinum based therapy --> contributed much
- PEB - cisplatin, etoposide, bleomycin x3 cycles --> lead to cure

Melanoma
- relatively drug resistant
- dacarbazine, temozolomide, cisplatin most active
- high dose IL-2 has led to cures

Secondary malignancies + cancer chemotherapy
- AML commonest, happens as learly as 2-4 yrs, peaks 5 + 9 yrs
- alkylating agents, procarbazine, etoposide, ionizing radiation --> all leukaemogenic
- others not that much