Chemotherapy blood-brain barriers

Cancer chemothCTapeutic agents as a rule poorly penetrate the blood brain barrier. Brain tumors are thus not readily treatable by chemotherapy. Diaziquone (at one time known as AZQ) is an exception to this generalization. Treatment of chloranil (213) with the anion from urethane gives intermediate 214, probably by an addition elimination scheme. Displacement of the remaining halogen with aziridine yields diaziquone (215) [.55J. 

Several reasons have been cited for the limitations of the use of chemotherapy in the treatment of malignant glioma. Inherent and acquired drug resistance and the lack of good drug penetration through the blood-brain barrier have both been cited as obstacles. Sev-... 

In an effort to overcome the lack of solubility, poor penetration across the blood-brain barrier and decreased delivery of conventional systemic agents by a compromised intratumoral blood supply, several studies have evaluated various combinations of BCNU alone or with other agents delivered intraarterally. Unfortunately, response rates and median survival times observed in patients treated with intraarterial chemotherapy have not been significantly different than those seen in patients treated with standard intravenous nitrosurea-containing regimens, while increased rates of toxicity such as leukoen-cephalopathy, retinal injury, edema, myelosuppression, sepsis, and thrombotic complications have been noted (40-46). 

The existence of the blood-brain barrier is an important consideration in the chemotherapy of neoplastic diseases of the brain or meninges. Poor drug penetration into the CNS has been a major cause of treatment failure in acute lymphocytic leukemia in children. Treatment programs for this disease now routinely employ craniospinal irradiation and intrathecally administered methotrexate as prophylactic measures for the prevention of relapses. The testes also are organs in which inadequate antitumor drug distribution can be a cause of relapse of an otherwise responsive tumor. 

Neuwelt, E.A., et al. 1994. Therapeutic dilemma of disseminated CNS germinoma and the potential of increased platinum-based chemotherapy delivery with osmotic blood-brain barrier disruption. Pediatr Neurosurg 21 16. 

Doolittle, N.D., Miner, M.E., Hall, W.A., Siegal, T., Jerome, E., Osztie, E., McAllister, L.D., Bubalo, J.S., Kraemer, D.F., Fortin, D., Nixon, R., Muldoon, L.L., and Neuwelt, E.A. (2000) Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood-brain barrier for the treatment of patients with malignant brain tumors. Cancer 88, 637-647. 

The treatment of choice for leukemia is chemotherapy, but because of the blood-brain barrier cytotoxic drugs are ineffective in treating leukemic optic neuropathy. Radiotherapy is the preferred treatment for the optic neittopathy because the optic nerve is relatively insensitive to radiotherapy but the leukemic cells are very radiosensitive. Chemotherapy and local irradiation have not shown promise in the treatment of lymphomatous optic neittopathy Meningiomas, likewise, are insensitive to chemotherapy and irradiation and require surgical excision. 

There has been considerable interest in the potential use of P-gp inhibition to optimize pharmacotherapy of anticancer and antiretroviral agents. Significant efforts have been made to exploit P-gp blockade in an effort to enhance chemotherapy uptake in tumors expressing P-gp-mediated drug resistance, to improve chemotherapy bioavailability, and to increase exposure to tumors protected by the blood-brain barrier. Research is also being directed at using P-gp inhibitors in HIV patients to improve protease inhibitor uptake into T-lymphocytes and virologic sanctuaries such as the brain and testes. 

A similarly depressing picture exists with tumours in the brain. Conventional anticancer chemotherapy often cannot penetrate the barrier to attack the tumour. The CNS, however, does require low-molecular-weight molecules to grow and function and these small polar molecules (e.g. amino acids, sugars) have their own transport proteins located at the blood-brain barrier that act to transfer the essential compound through the barrier in a process called carrier-mediated transport. 

Morikawa N, Mori T, Abe T, Kawashima H, Takeyama M, Hori S (1999) Pharmacokinetics of etoposide and carboplatin in cerebrospinal fluid and plasma during hyperosmotic disruption of the blood brain barrier and intraarterial combination chemotherapy. Biol Pharm Bull 22 428-431. 

Because the high risk of central nervous system relapse in ALL, all patients require prophylactic therapy to prevent CNS disease. The choice for therapy includes a combination of the following cranial irradiation and single-agent intrathecal chemotherapy, triple-drug intrathecal chemotherapy, or high-dose systemic chemotherapy that crosses the blood-brain barrier. 

Tretinoin, an oral vitamin A analog, is usually given orally in a dose of 45 mg/m per day, as a single dose or divided into two doses, given after a meal. Tretinoin-based regimens achieve CR rates as high as 95%in APL patients within 1 to 3 months. Tretinoin does not cross the blood-brain barrier therefore leukemic meningitis should be treated with conventional intrathecal chemotherapy. 

ALL is associated with infiltration of the CNS and testes (Sanctuary sites). Prophylactic radiation and/or chemotherapy to the head is recommended because malignant cells in brain are protected from chemotherapy by the blood-brain barrier. 

New folate antagonists have been identified that are better substrates for the reduced folate carrier and appear to have significant advantages in clinical chemotherapy (see pemetrexed below). In efforts to bypass the obligatory membrane transport system and to facilitate penetration of the blood—brain barrier, lipid-soluble folate antagonists also have been synthesized. Trime-trexate (NEVTREXIN) has modest antitumor activity, primarily in combination with leucovorin rescue. However, it is beneficial in the treatment Pneumocystis jiroveci pneumonia, where leucovorin provides differential rescue of the host but not the parasite. 

Fortin D, Desjardins A, Benko A, Niyonsega T, Boudrias M. Enhanced chemotherapy delivery by intraarterial infusion and blood-brain barrier disruption in malignant brain tumors the Sherbrooke experience. Cancer 2005 103 2606-2615. 

Does Castellon consider post-chemo changes a type of brain injury With the breast cancer patients I typically work with, many of the chemotherapy agents don t effectively cross the blood-brain barrier and directly injure the brain, he says. But could they cause indirect injury through immune system dysfunction, or vascular injury I would say yes. ... 

Certainly the blood-brain barrier should stop most chemotherapy cold, right at the gate. So, then, how are its toxins sneaking through ... 

Of course, we won t know in advance who will win the raffle and remain cognitively unscathed, and who will not. But just by addressing the questions, some of the riddle unfolds. We know that many cancer survivors experience cognitive problems that are debilitating. We also know that chemotherapy does not cross the blood-brain barrier in very high concentrations. .. at least when the blood-brain... 

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