Cisplatin and radiation in the treatment of tumors of the central nervous system: pharmacological considerations and results of early studies

Stewart, David J.; Molepo, J. M.; Eapen, Libni; Montpetit, V.; Goel, Rakesh; Wong, P. T. T.; Popovic, P.; Taylor, Kmg; Raaphorst, G. P.

doi:10.1016/0360-3016(94)90082-5

Cited by 34 publications

(20 citation statements)

References 60 publications

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“…We feel that the results obtained with these low-dose studies may well be applicable to the higher doses usually used clinicaly since the tumour platinum concentrations noted in this study were in the expected range when compared with our previous studies using higher doses of cisplatin (reviewed in Stewart et al., 1994a;Stewart, 1994), since cisplatin plasma pharmacokinetics is linear with dose (Vermorken et al, 1986), and since cisplatin accumulation in cells in vitro is linear with dose and is not saturable (Mann et al, 1990).…”

Section: D6cussionsupporting

confidence: 75%

“…al., 1994a;Stewart, 1994). For many chemotherapy drugs, only low concentrations are found in normal brain and cerebrospinal fluid (CSF), because of the BBB and blood-CSF barrier, but the barrier is often largely disrupted in patients with brain tumours (Blasberg and Groothuis, 1986).…”

Section: Sinarymentioning

confidence: 98%

“…Hence, it is possible that the conclusions we have drawn regarding total platinum concentrations do not also apply to the active species or to binding of drug to cytotoxcity-related intracellular targets. Despite this, we feel that the information gained is important, since we have previously found that both isplatin efficacy and toxicity are proportional to total tissue platinum concentrations (reviewed in Stewart, 1994a;Stewart, 1994), and since several cisplatin metabolites are cytotoxic (Goel and HowelL 1989). Based on these earlier observations, the concentration of active species is probably geneally proportional to the total platinum content.…”

Section: D6cussionmentioning

confidence: 99%

“…While the BBB is largely disrupted within intracranial tumours (Groothuis et al, 1981;Blasberg and Groothuis, 1986), degree of contrast enh nt on CT scans suggests that it may be less disrupted in low-grade than high-grade gliomas (Tchang et al, 1977). While some evidence suggests that the BBB plays a role in the resistance of human IC tumours to chemotherapy, there are alternative explanations for much of the evidence (reviewed in Stewart et al, 1994a;Stewart, 1994). Tumour cell resistance is probably a far more important reason for chemotherapy failure than is inability of the drug to cross the intact BBB, and any barrier might make relatively little difference for a highly cytotoxic drug (Wodinsky et al, 1977).…”

Section: D6cussionmentioning

confidence: 99%

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Factors affecting platinum concentrations in human surgical tumour specimens after cisplatin

Molepo²,

Rm³

et al. 1995

Br J Cancer

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SinaryWe asessed factors which affect cisplatin concentrations in human surgical tumour specmen. al., 1994a;Stewart, 1994). For many chemotherapy drugs, only low concentrations are found in normal brain and cerebrospinal fluid (CSF), because of the BBB and blood-CSF barrier, but the barrier is often largely disrupted in patients with brain tumours (Blasberg and Groothuis, 1986). In animal models, the degree of BBB disruption varies from one type of tumour to another and between parts of the same tumour (Groothuis et al., 1981;Blasberg and Groothuis, 1986). Lower concentrations of chemotherapy drugs (Levin et al., 1972;Tator, 1976;Groothuis et al., 1981) and lower capillary permeability (Hasegawa et al., 1983) It has also been argued that resistance of IC tumours may be due in part to invasion of tumour cells into the brain adjacent to tumour (BAT), where the BBB is more intact, and where drug concentrations are lower than in the main body of the tumour (Levin et al., 1975). However, the importance in brain tumour chemotherapy of resistance of tumour cells in the BAT remains controversial. Since even small numbers of tumour cells may induce leakiness in local blood vessels (Stewart et al., 1987), small tumour deposits in the BAT could result in a very localised increase in drug concentrations, and it is uncertain how drug concentrations compare in individual tumour cells in BAT vs the main tumour body.We have studied several chemotherapy drugs with respect to the concentrations reached in human IC tumours (reviewed in Stewart et al., 1994a, Stewart, 1994. Concentrations in IC tumours appeared to be similar to those in EC tumours for cisplatin, phosphonacetyl-L-aspartate, 4'-(9-acridinylamino)-methanesulphon-m-aniside (AMSA), pentamethylmeamine, doxorubicin and vinblasine. Concentrations of etoposide and mitoxantrone in IC tumours were somewhat lower than in EC tumours. Since no EC tumour samples were available, comparisons were not possible for a variety of other agents, but for most of these drugs potentially cytotoxic concentrations were achieved in human IC tumours. Low drug concentrations in normal brain and CSF did not preclude high concentrations in IC tumours.In this paper, we report the results of further studies of human tumour accumulation of the chemotherapy drug cisplatin. These studies were done since our earliest studies of surgical specimens had looked only at IC tumours. While our later autopsy studies had looked at both IC and EC tumours, there were differences between patients with respect to drug doses, time from last treatment to death, concurrent drugs, etc. (reviewed in Stewart et al., 1994a; Stewart, 1994). Hence, we conducted the studies reported in this paper so that a companson could be made between IC and EC tumours

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Section: D6cussionsupporting

confidence: 75%

Section: Sinarymentioning

confidence: 98%

Section: D6cussionmentioning

confidence: 99%

Section: D6cussionmentioning

confidence: 99%

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Factors affecting platinum concentrations in human surgical tumour specimens after cisplatin

Molepo²,

Rm³

et al. 1995

Br J Cancer

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“…Instead, the metabolites interact with the polar head groups and increase the distance betwen acyl chains. We have also shown that cisplatin could diffuse through a relatively fluid model membrane made from phosphatidylcholine (PC), but could not diffuse into more rigid model membranes made from phosphatidylethanolmine (PE) (Taylor et al, 1993;Stewart et al, 1994). In addition to PS, both PE and PC are of interest because concentrations of PE and PS are reported to be increased in the plasma membrane of DDP-resistant tumour cells, and concentrations of PC are reported to be very high in the plasma membranes of DDP-sensitive cells .…”

Section: Discussionmentioning

confidence: 99%

Pressure tuning infrared spectroscopic study of cisplatin-induced structural changes in a phosphatidylserine model membrane

Taylor

Goel²,

Shirazi³

et al. 1995

Br J Cancer

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Summary The dynamic effect of cis-diamminedichloroplatinum(II) (DPP) and its aquated metabolite (DDP-OH) on a dimyristoylphosphatidylserine (DMPS) model membrane was investigated by pressure tuning vibrational spectroscopy. The native species (DDP-C1) and the aquated species (DPP-OH) were both observed to bind to the carboxylate group of the serine as evidenced by a frequency shift of 1622-1620 cm '. However, only DDP-OH was observed to bind to the phosphate group (PO2-). The binding of either drug to DMPS resulted in an increased pressure required to halt the reorientational fluctuations of the acyl chains, indicating that the distance between the chains was increased. The two drugs did not partition into the matrix of the hydrophobic section in the model membrane. Collectively, these data suggest that DDP-C1 and DDP-OH are capable of binding to the polar head group of DMPS, resulting in an enlargement of the area of the head and a subsequent increase in the intermolecular distance between the acyl chains.

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Pressure-tuning fourier transform infrared spectroscopic study of carcinogenesis in human endometrium

et al. 1998

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Cisplatin and radiation in the treatment of tumors of the central nervous system: pharmacological considerations and results of early studies

Cited by 34 publications

References 60 publications

Factors affecting platinum concentrations in human surgical tumour specimens after cisplatin

Factors affecting platinum concentrations in human surgical tumour specimens after cisplatin

Pressure tuning infrared spectroscopic study of cisplatin-induced structural changes in a phosphatidylserine model membrane

Pressure-tuning fourier transform infrared spectroscopic study of carcinogenesis in human endometrium

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