Comparison of in vitro activity of epipodophyllotoxins with other chemotherapeutic agents in human medulloblastomas

Abstract

Summary Surgical specimens from 15 medulloblastoma patients were used to establish early passage cultures. In vitro sensitivity to a battery of cytotoxic agents, including some in current medulloblastoma treatment protocols, was measured. Drug sensitivity was assessed at clinically relevant drug concentrations using the 3H-thymidine uptake method. Tumours were predicted to be sensitive if >37% were killed by exposure to drugs at clinically achievable levels. A poor response to vincristine (Vcr), cis-platin (CDDP), hydroxyurea (HU) Medulloblastoma is an important paediatric brain tumour because of its high incidence and malignant behaviour. The overall disease free survival at 5 years, in patients receiving surgery and craniospinal axis radiotherapy, is approximately 50%. This is considered to be the upper limit of curability by these treatment modalities. Chemotherapy has been shown to be advantageous in selected patient groups either as adjuvant therapy or as treatment of recurrent disease. The value of chemotherapy in the treatment of medulloblastoma will be dependent on the availability and identification of drugs active against this tumour. At present, protocols for chemotherapy usually include the lipophilic compounds carmustine (BCNU) or lomustine and procarbazine. Vincristine (Vcr), whilst poorly absorbed by cerebrospinal fluid and brain, is also commonly used (Bloom, 1986;Workman, 1986). Currently '8 in 1F therapy is being evaluated (Pendergrass et al., 1987).Cytotoxicity has been assessed by clonal assays in agar or on plastic, incorporation of 3H-thymidine into DNA, uptake of vital dyes and other methods with much the same results. Predictions of resistance are close to 100% correct; prediction of sensitivity, whilst less reliable, still has a success rate of around 70% Moon et al., 1981; Rosenbloom et al., 1983;Bogdahn, 1983;Kornblith et al., 1981;Kimmel et al., 1987). We have examined drug sensitivity in human medulloblastoma by using 14 early passage cultures. Our study provides data on the degree of heterogeneity of response between medulloblastomas obtained from a number of patients. Furthermore, the cells were from early passage cultures, and hence should give a better indication of chemosensitivity of the tumours in vivo. The epipodophyllotoxins teniposide (VM-26) and etoposide (VP16-213) were identified as potentially useful agents in this disease. We investigated the basis of primary clinical resistance to these drugs by quantitating intracellular steady-state drug concentrations, drug-induced protein-linked DNA strand breaks, and topoisomerase II expression and activity. Materials and methods Establishment of cell culturesAll studies were made on material collected at procedures performed for clinical reasons and remaining after sufficient tissue has been taken for clinical laboratory study. The histological diagnosis was confirmed by an independent neuropathologist (Professor B.W. Scheithauer). Over a period of 2 years, 16 medulloblastoma specimens were received from a total of 15 patients...

Etoposide Treatment in Recurrent Medulloblastoma

“…Etoposide as a single agent has been used in progressive or relapsed primary brain tumors, mainly highgrade gliomas: Effectivity was low (10, 20) or missing (9). Cell cultures of surgical specimens from medulloblastoma patients are sensitive to clinically achievable concentrations of the epipodophyllotoxins teniposide (VM-26) and to a lesser extent to etoposide (21). Etoposide levels in the CSF after intravenous administration are low (4, 6, 7, 13) or undetectable (23); etoposide concentrations in peritumoral brain tissue are low (23).…”

“…Combination of cisplatin (15) or carboplatin (3) with etoposide (VPl6-213) has been proposed in recurrent medulloblastoma. Sensitivity of medulloblastoma cells to etoposide has been demonstrated in vitro (21) . Clinical data concerning etoposide as a single agent in medulloblastoma are missing.…”

Developing options for method of assessing the sensitivity of cells intracranial neoplasms to chemotherapeutics in vitro

“…Это предопределило предпочтительность выбора в пользу ТВ тестирования. Принимая во внимание перечисленное, в указанный метод были привнесе-ны модификации, позволяющие обойти очерчен-ные «ловушки» и адаптировать его применительно к интракраниальным неоплазиям, поскольку боль-шинство анализов разрабатывалось на основе рака кроветворной и лимфоидной систем [3,7,9], тогда как мозговым опухолям уделялось гораздо более скромное внимание [1,29,33,39,42,45].…”

Research of the intracranial neoplasia cell sensitivity to chemotherapy drugs

“…Операционное удаление интракраниальных неоплазий не всегда возможно из-за опасности повре-ждения жизненно важных центров или диффузной их локализации, что делает актуальным совершенство-вание методов лучевой и химиотерапии. Наиболее эффективными для лечения нейроэпителиальных опухолей признаны следующие химиопрепараты: цисплатин, карбоплатин, темозоломид, этопозид, метотрексат, цитарабин [5][6][7][8].…”