Factors affecting platinum concentrations in human surgical tumour specimens after cisplatin

Abstract

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

Brain Metastases: The HER2 Paradigm

“…Although most cytotoxic agents do not cross the blood-brain barrier under normal conditions, there is evidence that the blood-tumor barrier is far more permissive (71,72). Therefore, it is likely that responses in the CNS are influenced by similar considerations as systemic response, such as prior therapy and the biological characteristics of the tumor.…”

Biodistribution of cisplatin revealed by imaging mass cytometry identifies extensive collagen binding in tumor and normal tissues

“…Previous studies have used bulk assays to measure the amount of Pt in tissues obtained from patients following cisplatin treatment17, with little information available about the localization of cisplatin within the tumor microenvironment and in normal tissues. Mass cytometry is able to detect elements in the mass range 75–209, and we have previously described its use to measure the uptake of platinum-based drugs in cell suspensions from human tumor xenografts18.…”

Phase II Trial of Lapatinib for Brain Metastases in Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer

“…14,15 Although neither gefitinib nor lapatinib cross the intact blood-brain barrier to a significant degree in pre-clinical models, the blood-tumor barrier may be more permissive, leading to the hypothesis that lapatinib may have activity in established CNS disease. 16,17 We conducted a phase II study to evaluate the clinical efficacy and adverse-effect profile of lapatinib in the treatment of women with brain metastases from HER-2-positive breast cancer. On the basis of the activity of lapatinib in refractory breast cancer, and its structural similarity to gefitinib, we hypothesized that lapatinib would be active in women with HER-2-positive breast cancer metastatic to the brain.…”