Difficulties in predicting drug sensitivity and tumour response to the - PDF document

1 Difficulties in predicting drug sensitiv
Difficulties in predicting drug sensitivity and tumour response to therapy might be a result of the complex microarchitecture within tumours, as it affects drug diffu-sion and distribution. To solve this problem, two different devices have been developed recently that deliver cancer drugs directly into tumours invivo, thereby enabling assessment of drug distribution as well as of cytotoxic effects on cancercells.Jonas etal. created a small cylin-der with up to 16 reservoirs that can be implanted with a standard biopsy needle directly into mouse tumours, where it remains for 24hours. Each reservoir — adequately separated from the next one so that the drugs did not mix — immediately released the drug (or combination of drugs) passively into the surrounding tumour tissue. The device and its sur-rounding tissue were then removed with a larger needle to assess whether the cancer cells had responded to the drugs. The authors tested the device with different doses of doxorubicin, lapatinib and cetuximab, among other agents, in xenografts of human breast carcinoma cells and observed a steady gradient of drug distribution within 300–400 m of the device. They then sought to identify the minimum intratumour drug levels required to induce apoptosis, meas-ured by cleavage of caspase 3, and found that these varied significantly between different tumour models. In doxorubicin-sensitive xenografts from melanoma cells, for example, drug exposure for 14hours at clini-cally relevant concentrations led to apoptosis of nearly all cells within 250 m of thedevice. each left a 6 - mm track containing a drug and a co-injected inert track-ing dye that enabled assessment of consistency of tumour response to the drug across multiple tissue depths. After drug injection and incubation insitu, the tumour tissue was excised, and the effects of the drug on cancer cells were measured by an automated analytical package coupled to thedevice.The authors used different xeno-graft models (lymphoma and two models of non-small cell lung cancer) and monitored the phamacodynamic effects of vincristine, doxorubicin and prednisolone. As Jonas etal., the authors evaluated whether localized tumour responses correlated with responses to systemic delivery of drugs. They used a variant of the lym-phoma line that is refractory to doxo-rubicin and found that short-term (1–3days) responses to the CHOP regimen — doxorubicin, vincristine, mafosfamide and prednisolone — evaluated with CIVO were similar to longer-term (up to 29days) systemic responses. Klinghoffer etal. also checked the sensitivity of their lym-phoma models to 97 approved cancer drugs and found that the resistant cells were most sensitive to mTOR inhibitors, which also correlated with the systemic tumour response.Finally, Klinghoffer etal. tested the CIVO platform in 4 patients, showing the feasibility of the approach to inject superficial tumours (lymph nodes) and evaluate cancer cell death after 24hours. This preliminary assess-ment in patients indicated that the insertion of the device was well toler-ated and safe; a larger clinical trial is now planned forCIVO.These two techniques are able to evaluate cell penetration by drugs and drug stability, as well as screen many drugs to find the most effec-tive one. Importantly, they are also able to assess dose–response curves, which can help clinicians to deter-mine the dose of a drug that has the best risk–benefit profile.M.Teresa Villanueva DRUG DELIVERYGet in there! ORIGINAL RESEARCH PAPERS Jonas, O.GV|CN An implantable microdevice to perform high-throughput KP|XKXQ drug sensitivity testing in tumors. 5EK6TCPUN/GF 7, 284ra57 (2015) | Klinghoffer, R. A. GV|CNA technology platform to assess multiple cancer agents simultaneously within a patient’s tumor. 5EK6TCPUN/GF 7, 284ra58 (2015)These two techniques are able to evaluate cell penetration by drugs and drug stability, as well as screen many drugs to find the most effective oneLara Crow/NPG © 2015 Macmillan Publishers Limited. All rights reserved © 2015 Macmillan Publishers Limited. All rights reserved ONLINE ONLY