Problema de empaquetado

1 40 -

Drug dose (pg/ml)

Low grade pilocytic astrocytoma High grade astrocytoma

M edulloblastom a Neuroblastoma

Procarbazine

Fig 28b represents the meaned dose response curves of the different tumour types

studied against PCB. The number of cultures comprised of 7 ependymoma/ 6 pilocytic and 5

high grade astrocytom as, 12 m edulloblastom a and 2 neuroblastomas. All tumour types responded in virtually the same manner. Fig 29b shows the chem osensitivity profiles of th e cultures to PCB. All tumour types appeared to have rather sim ilar sensitivities to this drug w ith the exception of Daoy and TE671 (Table 15). The m edulloblastom as showed the w id est

range of sensitivitities w ith ID50 values ranging from 905-17070 p g /m l, about a 19-fold

difference. Daoy was one of the most resistant cell lines to this drug, w ith an ID50 value of

5083 p g /m l. One short-term cell line from the MB group of tumours h ad the highest value of 17070 p g /m l, and a num ber of cultures had values greater than 3000 pg/m l. The ependymom as

show ed less variation in sensitivity w ith ID50 values betw een 1347 and 2842 p g /m l. The most

sensitive cell line h ad a value of 1347 pg/m l, w hilst the rem ainder of cultures were found to fall into a range betw een 2400-3022 p g /m l. The heterogeneity of values w ithin this group w as not as pronounced as for m edulloblastom as. Pilocytic astrocytom as, h ad a range of 1987-3202 pg/m l. The values fell into three distinct groups, one less than 2000 p g /m l, another w i t h values greater than 2400 pg/m l and finally those w ith greater than 3100 pg/m l. In contrast, the high grade astrocytom as did display a degree of heterogeneity w ith a range of values

between 468-2952 pg/m l, a 6-fold difference. Finally, the two neuroblastom a cultures, h a d

ID50 values of 2374 and 3847 p g /m l.

Comparisons of m edian ID50 values between different tumour histologies, show ed

th at high grade astrocytomas were more sensitive (m edian 1641 pg/m l) than the pilocytic astrocytom as (median 2573 pg/m l). Ependymomas and pilocytic astrocytom as h ad sim ila r

m edian values (>2500 pg/m l) and they were both slightly more resistant th a n

m edulloblastom as (median 2468 pg/m l). Neuroblastom as were the most resistant of all th e short-term cultures (median 3110pg/ml, see Table 15). In contrast to the short-term cell lines, Daoy and TE671 were extremely resistant to PCB (median 5083 and 4672 pg /m l resp ectiv ely . Fig. 30b). Ependymomas were more resistant than hig h grade astrocytom as (p=0.017) and Daoy (p=0.05) to PCB, but the difference between the other tumour groups did not re a c h significance. TE671 was consistently m ore resistant to PCB than high (p=0.04) and low grade pilocytic astrocytom as (p=0.03) and m edulloblastom as (p=0.03). Also TE671 w as more resistant to PCB than ependym om as (p=0.008).

V incristine

Fig 28c shows the meaned dose response curves to VCR for the different tumour types.

The data was comprised of 5 ependymoma, 6 pilocytic and 5 high grade astrocytom a, 11

m edulloblastom a and 2 neuroblastoma cultures. G reater heterogeneity between this drug compared to CCNU or PCb was observed in the cultures response to VCR. Fig 29c shows th e

same tumour group were seen w ith VCR. Extreme sensitivity to VCR was shown by

neuroblastomas w ith ID50 values between l.lxlO""^ - 1.7x10"^ |ig/m l. In contrast,

ependymomas were extremely resistant w ith ID50S between 1.9x10"^ - l.SxlO"^ |ig/m l. The

high grade astrocytom as (5.5x10""^ - 4.1x10“^ pg/m l), m edulloblastom as (3.2x10"^ - 4.8x10"^ pg /m l) and low grade pilocytic astrocytomas (1.4x10"^ - 1.2x10"^ pg/m l) were of sim ilar and interm ediate sensitivity.

M edulloblastom as displayed a 15-fold difference from the m ost sensitive to the most resistant. H igh grade and pilocytic astrocytomas showed a 7-fold and 21-fold difference respectively, and ependymomas displayed a 9-fold difference between the most and le a s t resistant. In addition, the neuroblastomas showed a 16-fold difference between the most sensitive and the m ost resistant. However, there were only tw o such samples.

The m edian IDgo's for m edulloblastom as, pilocytic and high grade astrocytom as was

very similar (> 0.0015 p g /m l, see Table 13). The high grade astrocytom as h ad a m edian ID50

of 0.0022 pg /m l and the pilocytic astrocytomas h ad a m edian ID50 of 0.0015 pg/m l. The ependymomas, the most resistant of all the short-term cell lines h a d a m edian of 0.0042 p g /m l. Ependym om a cultures were significantly more resistant than MBs (p=0.026), low grade pilocytic astrocytom as (p=0.041), and neuroblastom as (p=0.041). How ever, difference betw een the high grade astrocyotmas and ependym om as did not reach significance (p=0.088).

Daoy h ad a m edian 2-fold greater than th at of short-term cell lines derived from m edulloblastom as (0.0046 pg/m l). In contrast, the cell line, TE671 was found to be the most sensitive, w ith a m edian of only 0.0007 p g /m l (Fig. 30c). Again TE671 w as significantly more sensitive to VCR than the other tumour groups; ependymomas (p=0.0045), high grade

astrocytom as (p=0.01), but only slightly more sensitive than the only p rim itiv e

neuroepithelial tumour studied (p=0.05). The difference in response to VCR between TE671 and the MB cultures approached significance (p=0.08).

Fig 29a

This graph shows the distribution of response of cultures derived