The in vitro effect of gefitinib ('Iressa') alone and in combination with cytotoxic chemotherapy on human solid tumours.
BACKGROUND
Activation of the epidermal growth factor receptor (EGFR) triggers downstream signaling pathways that regulate many cellular processes involved in tumour survival and growth. Gefitinib ('Iressa') is an orally active tyrosine kinase inhibitor (TKI) targeted to the ATP-binding domain of EGFR (HER1; erbB1).


METHODS
In this study we have used a standardised ATP-based tumour chemosensitivity assay (ATP-TCA) to measure the activity of gefitinib alone or in combination with different cytotoxic drugs (cisplatin, gemcitabine, oxaliplatin and treosulfan) against a variety of solid tumours (n = 86), including breast, colorectal, oesophageal and ovarian cancer, carcinoma of unknown primary site, cutaneous and uveal melanoma, non-small cell lung cancer (NSCLC) and sarcoma. The IC50 and IC90 were calculated for each single agent or combination. To allow comparison between samples the IndexSUM was calculated based on the percentage tumour growth inhibition (TGI) at each test drug concentration (TDC). Gefitinib was tested at concentrations ranging from 0.0625-2 microM (TDC = 0.446 microg/ml). This study represents the first use of a TKI in the assay.


RESULTS
There was heterogeneity in the degree of TGI observed when tumours were tested against single agent gefitinib. 7% (6/86) of tumours exhibited considerable inhibition, but most showed a more modest response resulting in a low TGI. The median IC50 value for single agent gefitinib in all tumours tested was 3.98 microM. Interestingly, gefitinib had both positive and negative effects when used in combination with different cytotoxics. In 59% (45/76) of tumours tested, the addition of gefitinib appeared to potentiate the effect of the cytotoxic agent or combination (of these, 11% (5/45) had a >50% decrease in their IndexSUM). In 38% of tumours (29/76), the TGI was decreased when the combination of gefitinib + cytotoxic was used in comparison to the cytotoxic alone. In the remaining 3% (2/76) there was no change observed.


CONCLUSIONS
The in vitro model suggests that gefitinib may have differential effects in response to concomitant cytotoxic chemotherapy with the agents tested during this study. The mechanism involved may relate to the effect of TKIs on growth rate versus their effect on the ability of the cell to survive the stimulus to apoptosis produced by chemotherapy.
Knight
Louise A
LA
Translational Oncology Research Centre, Department of Histopathology, Queen Alexandra Hospital, Portsmouth, UK. louise.knight@porthosp.nhs.uk
Di Nicolantonio
Federica
F
Whitehouse
Pauline
P
Mercer
Stuart
S
Sharma
Sanjay
S
Glaysher
Sharon
S
Johnson
Penny
P
Cree
Ian A
IA
D000230:Adenocarcinoma / Q000188:drug therapy; D000255:Adenosine Triphosphate / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy; D002066:Busulfan / Q000008:administration & dosage / Q000031:analogs & derivatives*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D002945:Cisplatin / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008545:Melanoma / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy*; D009382:Neoplasms, Unknown Primary / Q000188:drug therapy; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D010051:Ovarian Neoplasms / Q000188:drug therapy; D000077150:Oxaliplatin; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D012509:Sarcoma / Q000188:drug therapy; D012878:Skin Neoplasms / Q000188:drug therapy; D013274:Stomach Neoplasms / Q000188:drug therapy; D014604:Uveal Neoplasms / Q000188:drug therapy; D000093542:Gemcitabine
D009944:Organoplatinum Compounds; D011799:Quinazolines; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000255:Adenosine Triphosphate; C018404:treosulfan; D002066:Busulfan; D002945:Cisplatin; D000077156:Gefitinib; D000093542:Gemcitabine