The establishment, characterization and calibration of human ovarian carcinoma xenografts for the evaluation of novel platinum anticancer drugs

Abstract

Twenty-three serially transplantable ovarian carcinoma xenografts have been established in female nude mice from forty-two donor samples provided by both previously treated and untreated patients. The lines are all of human karyotype and mirror the histopathology of the original explant. Sixteen examples have been calibrated against four reference platinum drugs: cisplatin, carboplatin, iproplatin, tetraplatin. Three distinct patterns of response were observed: (i) tumours which were comparably sensitive to all four drugs (2 lines); (ii) tumours which were comparably refractory to treatment with all four drugs (5 lines); (iii) tumours which exhibited "individual" patterns of response to the group of calibrating drugs (9 lines). The "response rate" overall of the tumour panel to each of the clinically used drugs was 44% (7/16), though the pattern of response was not identical for each drug. Only 2/16 tumours (13%) were sensitive to tetraplatin, these also being the same tumours which were particularly sensitive to the other three drugs. It was also possible to confirm in 8/9 lines that the therapeutic response of the xenograft reflected that of the corresponding patient's tumour to platinum-based chemotherapy. This tumour panel has now been adopted for evaluating novel platinum-based drugs designed specifically for the treatment of ovarian cancer.

Characterisation of molecular events following cisplatin treatment of two curable ovarian cancer models: contrasting role for p53 induction and apoptosis in vivo

“…By contrast, the pxn100 xenograft was derived from an endodermal sinus tumour and was germ cell in origin. Their xenograft histologies reflected those of the tumour of origin (Harrap et al, 1990). The pxn65 and pxn100 human ovarian cancer xenografts were passsaged as or grown for treatment from 2 mm 3 biopsy fragments implanted s.c. in anaesthetised female nude (random bred) mice (age 6 -8 weeks).…”

“…A previous study of 16 ovarian tumours established as in vivo xenograft tumours direct from tumour biopsy material had established their relative sensitivity to treatment with four platinum-based agents (Harrap et al, 1990). Two of the 16 tumours, pxn65 and pxn100, were found to be highly chemosensitive and curable following treatment with multiple doses of CDDP close to those commonly used in the clinic (Harrap et al, 1990 and unpublished).…”

“…The majority of ovarian cancers are epithelial in origin and pxn65, derived from a moderately differentiated adenocarcinoma, belonged to this class. The biopsy was derived from a previously untreated patient who went on to show a complete remission with CDDP (Harrap et al, 1990). Pxn100 was derived from an endodermal sinus tumour and was germ cell in origin.…”

“…Pxn100 was derived from an endodermal sinus tumour and was germ cell in origin. This biopsy was taken from a patient who showed complete remission to a number of platinum-based combination therapies prior to biopsy (Harrap et al, 1990). These two lines would not grow as monolayer cultures in vitro and could only be passaged as in vivo xenografts where their response and histopathology as a xenograft closely paralleled that observed in the clinic (Harrap et al, 1990).…”

“…This biopsy was taken from a patient who showed complete remission to a number of platinum-based combination therapies prior to biopsy (Harrap et al, 1990). These two lines would not grow as monolayer cultures in vitro and could only be passaged as in vivo xenografts where their response and histopathology as a xenograft closely paralleled that observed in the clinic (Harrap et al, 1990). Therefore, pxn65 and pxn100 provided a valuable opportunity to study cellular and molecular events associated with CDDP treatment in highly sensitive, curable, in vivo models of human ovarian cancer.…”