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The Oncologist, Vol. 4, No. 2, 112-121, April 1999
© 1999 AlphaMed Press

Cytoprotection: Shelter from the Storm

Paula Klein, Franco M. Muggia

Kaplan Comprehensive Cancer Center, New York University Medical Center, New York City, New York, USA

The narrow selectivity of anticancer drugs became obvious to clinical investigators shortly after the introduction of cancer chemotherapy 50 years ago. Therefore, it is not surprising that ever since preclinical and clinical studies have addressed the concept of selective rescue in healthy tissues.

Historically, the concept of cytoprotection came into being with the use of leucovorin (LV) or citrovorum factor (CF) as a cytoprotectant with methotrexate (MTX). Briefly, MTX blocks the enzyme dihydrofolate reductase, which is necessary for the synthesis of tetrahydrofolate and other forms of reduced folates. Tetrahydrofolate and related cofactors are essential in the transfer of carbon units in many biochemical reactions such as the conversion of deoxyuridylate to thymidylate in DNA synthesis. CF effectively bypasses the block by supplying tetrahydrofolate.

The murine leukaemia L1210 experiments performed by the father of experimental chemotherapy, Abraham Goldin and co-workers showed increased survival times in animals receiving the folate antagonist (FA) aminopterin along with delayed administration of LV compared to those treated with FA alone. Studies were then conducted with MTX and MTX with CF, in mice. CF fulfilled the criteria for an ideal cytoprotectant as it improved the therapeutic index by diminishing toxicity without compromising efficacy and without untoward side effects.

This original rescue concept was brought into the clinic when Djerassi et al. and Hryniuk et al. applied massive doses of MTX followed by LV in the treatment of human leukaemia. There were less toxic effects, particularly stomatitis, in those receiving LV compared with those patients who did not. High-dose MTX regimens (50 mg/kg or more) with LV rescue have produced responses in metastatic osteogenic sarcoma and other tumours.

Further characterization of MTX's biochemical effects led to other rescue strategies. For example, thymine-less death is presumed to occur in normal cells, whereas MTX-induced tumour cell death is related to purine deficiency. Thus, thymidine plus MTX would theoretically be useful against cancers with low endogenous purine levels compared to host cells. Also, asparaginase administered before MTX ameliorates toxicity, presumably by inhibiting cellular protein synthesis and by decreasing MTX uptake or retention in normal tissues. Clinical trials have demonstrated some usefulness of the combination against leukaemia but not against solid tumours.

The clinical introduction of the strikingly effective anthracycline antibiotics in the late 1960s and their unusual toxic effects (extravasation skin necrosis and cumulative cardiotoxicity) stimulated research on the underlying mechanisms. The use of animal models in the late 1970s and early 1980s led to the successful identification of dexrazoxane for the protection of anthracycline-induced cardiac damage. This achievement was a great stimulus for applying mechanistic and pharmacological principles in evolving a cytoprotective strategy to improve the therapeutic index of anticancer drugs.

In a parallel development, drugs expressly created as protectors against ionizing radiation were a further stimulus to the wider application of cytoprotection in cancer treatment. Early on, Patt et al. demonstrated that pretreatment with cysteine could protect rats from lethal radiation. Subsequently, during the cold war, the U.S. Walter Reed Army Institute of Research tested many compounds as radioprotectants. WR-2721, also known as amifostine, an analogue of cysteamine, was chosen from over 4,000 compounds for its radioprotective properties and safety. To have an effect WR-2721 must first be dephosphorylated by cellmembrane bound alkaline phosphatase to WR-1065, the active metabolite. The selective protection of normal cells, compared to tumour cells, can be explained by the much higher concentration of alkaline phosphatase in normal tissues and by their neutral pH, relative to the acidic pH in tumour cells. A neutral pH favours enzymatic conversion to the active drug. After dephosphorylation, the resulting WR-1065 is taken up rapidly into normal tissues but uptake occurs at a much slower rate in tumours.

After successful animal studies, clinical trials investigating WR-2721 with palliative radiotherapy were initiated. Subsequently trials were begun into the ability of WR-2721 to protect against the toxic effects of cyclophosphamide and, later, cisplatin. Protection against myelosuppression and nephrotoxicity were observed. Further studies have suggested that WR-2721 has cytoprotective effects against carboplatin, anthracyclines and taxanes, but results are preliminary and need confirmation.

As clinical methods in drug development increasingly relied on knowledge of mechanisms of action and of pharmacological principles in establishing the optimal dosescheduling of an agent, interest grew in precisely delineating the mechanisms of toxicity. In turn, clinical investigators began concommitantly to consider dose-intensification as well as cytoprotection.


   General Pharmacological Principles
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Current Clinical Applications
 Applications Under Development
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Pharmacologically directed rescue is exemplified by the use of MTX with LV rescue because clear pharmacological parameters have been established to minimize toxicity in the host. Stoller determined MTX concentrations in plasma following moderately high doses and identified patients at high risk for toxicity. These patients benefitted most from supplemental LV rescue. Because MTX concentrations above 1 x 10–8 inhibit DNA synthesis in bone marrow and intestinal epithelium, it seemed reasonable to continue LV rescue in patients suffering from toxic effects until plasma MTX fell below this level. Thus, in current high-dose MTX treatment, LV rescue has been tailored to pharmacological findings.

Phase I trials with new anticancer drugs have evolved methods that rely principally on the identification of doselimiting toxicities (DLTs). These DLTs encompass haematological and nonhaematological toxicities. Haematological DLTs often result in toxic effects on the neutrophil series which reduces concentrations to below 500/µL for more than five days. Any platelet count below 25000/µL is considered a DLT. For nonhaematological toxicity, the threshold is usually set at Grade 3 of the National Cancer Institute Common Toxicity Criteria or worse, with the exception of toxic effects that might be reversed or ameliorated with supportive care (e.g. antiemetics, technically a form of protector). Using the concept of DLTs, maximum tolerated doses or MTDs (usually when two or more of six patients manifest a DLT) may be established both in the absence and in the presence of a cytoprotective agent. Recently these strategies have been widely applied for agents whose DLT involves neutropenia, leading to the determination of an MTD without and with the use of a granulocyte-colony stimulating factor.

A clear relationship between the dose schedule and toxicity in certain (e.g. renewing) tissues has repeatedly emerged in the study of antifolates and antimetabolites. It was possible to give methotrexate in higher doses with intermittent schedules, presumably because of a reduced toxic insult to the gastrointestinal tract. On the other hand, anthracyclines, such as doxorubicin, administered by continuous infusion over several days yielded less cardiotoxicity.

With the introduction of cytokines to ameliorate myelosuppression, another rationale for dose scheduling was introduced to allow sufficient time for cytokines to exert their actions. With administration of a cytoprotective agent, the timing relative to the administration of the cytotoxic drug is crucial. Amifostine has a very short half-life (of the order of minutes) and must be given within 30 minutes of cisplatin administration for effective cytoprotection. Similar considerations determine the scheduling of dexrazoxane, before anthracyclines. With dexrazoxane, protection against doxorubicin cardiotoxicity may occasionally be incomplete because of doxorubicin's long half-life. Epirubicin is more completely eliminated by glucuronidation and may have its toxicity better curtailed by dexrazoxane pretreatment.

The pharmacological principle of systemic protection during locoregional drug administration was first applied when the intrathecal administration of MTX was followed by the systemic administration of LV. Carboxypeptidase-B was also used for this purpose, while more recently it has been used for accidental overdoses of MTX.

This pharmacological principle has also been employed with the intraperitoneal administration of cytotoxic drugs. Initially, Howell's group reported on the systemic administration of LV, while dwells of MTX provided locoregional exposure to high doses of the drug. The same group used sodium thiosulphate to neutralize cisplatin in the renal tubules, while high drug doses (up to 200 mg/m2) were routinely achieved intraperitoneally. Reactive platinum species in the blood were found to be higher than after systemic administration, suggesting selective protection of the kidney, selective cisplatin toxicity and an actual enhancement of both systemic and intraperitoneal antitumour effects. The studies stimulated interest in thiols, especially amifostine and newer cytoprotectors that do not neutralize cisplatin to the same extent as sodium thiosulphate.

Since it is comprised of rapidly renewing tissue, the gastrointestinal tract is susceptible to the toxic effects of fluoropyrimidines and antifolates. A non-absorbable agent, oxonic acid, has been developed to protect against the activation of fluoropyrimidines in the intestine. Enterohepatic recirculation of drugs such as the topoisomerase-1-inhibitor, CPT-11, may also augment gastrointestinal toxicities. Agents such as cyclosporin may ameliorate the diarrhoea caused by this agent by lowering exposure from biliary excretion.

The treatment of local toxicities to the lacrimal glands from antimetabolites has occasionally been tried using topical uridine or thymidine. Methods for decreasing freeradical formation and/or quenching have been used for the local toxicity of anthracycline skin extravasation and for the cardiotoxicity. Amifostine and glutathione have been found to diminish sensory neuropathies caused by cisplatin. Finally, steroids have been clearly shown to ameliorate the enhanced capillary leakage and lower-extremity oedema induced by docetaxel.


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Initial clinical trials have suggested that cumulative doses of doxorubicin are associated with cardiomyopathy, congestive heart failure and a typical histological lesion. The toxicity can be acute or chronic but more often it is chronic, appearing after the last cycle has been administered. The effects are clearly dose-related and have originally been reported to occur for dosages above 550 mg/m2. As an alternative to using specific dose ceilings, one can employ left ventricular ejection fraction changes as a measure of ensuing cardiotoxic effects.

Following convincing preclinical studies, randomized dexrazoxane trials demonstrated effective cardioprotection without loss of antitumour efficacy in the 1980s. Confirmatory trials established that a lower dose of dexrazoxane could be equally efficacious and that the cardioprotective benefit of dexrazoxane remained even after a cumulative dose of doxorubicin of 300 mg/m2 had been reached. Since then, it has been approved by the U.S. Food and Drug Administration for use in women with breast cancer receiving doxorubicin-based chemotherapy after a cumulative dose of 300 mg/m2. Current trials are evaluating its use in extended doxorubicin treatment in metastatic breast cancer; its cardioprotective effect for combinations of drugs with doxorubicin, and its use in the paediatric population where late cardiotoxicity is a major concern.

Preclinical animal studies have demonstrated that the administration of amifostine can protect against the nephrotoxic effects of cisplatin. Clinical trials have corroborated these studies, showing nephroprotection without a loss of anti-tumour activity. A phase III trial in advanced ovarian cancer, comparing cyclophosphamide and cisplatin with and without amifostine, showed a higher response rate with amifostine and equal overall survival but with significantly less of the serum creatinine elevations which require a delay in or discontinuation of cisplatin treatment in cycles five and six. In addition to protection against nephrotoxicity, there were fewer neutropenic events, which meant that patients had fewer days in hospital or on antibiotics for neutropenic events. The incidence and severity of toxic neurological effects following the last cycle of chemotherapy were also significantly reduced in the amifostine arm.

Animal studies have shown impressive radioprotection at bone marrow and mucosal sites, particularly the salivary glands, with the use of amifostine. Initial studies in Japan demonstrated that amifostine was helpful in treating acute radiation mucositis. The findings prompted investigations of the effect of amifostine in preventing chronic radiation damage. Using the uptake of Ga-67citrate as a measure of radiation injury in the salivary glands during head-and-neck treatment, investigators were able to demonstrate a significant decrease in Ga-67 uptake in the treatment group receiving amifostine compared with those not receiving amifostine, suggesting a radioprotective effect. Phase II studies were begun in the U.S. in head-and-neck cancer patients receiving a radiation dose of more than 45 Gy to the salivary glands. Using 99mTc pertechnetate scans of the salivary glands, the measurement of salivary flow rates showed a more impressive return to function compared to historical controls. A phase III study is now accruing patients with oropharyngeal, nasopharyngeal, and oral cavity primary cancers who are receiving 63 to 70 Gy with 200 mg/m2 amifostine prior to each radiation fraction. The aim is to demonstrate the effectiveness of this agent in reducing xerostomia and mucositis and to define further the toxicity profile of the drug when it is given on such a frequent basis.

During the 1970s, doxorubicin was noted to cause skin changes after inadvertent paravenous infiltration during administration. The cellular damage caused by doxorubicin is due both to intercalation into the (DNA) base structure and into its quinone structure, which can be reduced to free radicals. Local skin necrosis at the site of infusion is an infrequent but serious complication. Ulcers may progress to involve deep structures, exposing bone, tendons and nerves. Treatment usually involves early and extensive surgical debridement followed by skin grafting or flap coverage. A potential use for drugs that alter free radical damage from anthracyclines is administering immediate local treatment following extravasation.


   Applications Under Development
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The clinical applications of the cytoprotectors and rescue agents described are just initial landmarks in an emerging field of therapeutics. A number of other strategies, involving the protection of normal tissues, have already advanced into the clinic and even more are the focus of preclinical investigations.

Enhanced fluoropyrimidine systemic exposure appears achievable through the use of prodrugs such as Tegafur and through the use of protective agents such as oxonic acid in the development of the newly introduced S-1 drug formulation. Whether this will lead to improved therapeutic results awaits studies beyond phases I and II. Another effort to improve the therapeutic index of fluoropyrimidines relates to uridine rescue.

The reduced toxicity achieved with cyclosporin means that it is possible to increase the dose of CPT-11. Since gastrointestinal toxicity is reduced, a myelosuppressive doselimiting toxicity is reached at these higher doses, but the therapeutic advantage of such dose-intensification still needs to be documented.

Several attempts at enhancing the therapeutic index of cisplatin have been ongoing for years, as noted earlier. Platinum cytoprotectors may enhance the interest that has developed in using amifostine for the safer delivery of cisplatin combinations with gemcitabine or with topotecan. Combinations of gemcitabine and cisplatin have shown an activity against bladder, ovarian, and lung cancers which is suggestive of therapeutic synergism. The use of a cytoprotector would enable the safe delivery of these combinations since amifostine has been shown to protect against both the myelosuppression caused by a variety of chemotherapeutic agents and the nephrotoxic effects of cisplatin. Ongoing studies are comparing the toxicity of a gemcitabinecisplatin combination with and without amifostine. Recently, the mesna derivative dimesna has been shown to be an effective and selective modulator of cisplatin toxicity and may further facilitate this strategy.

Increasingly, differences between cell cycle control in normal and malignant cells have become better delineated. As a result, preclinical strategies based on protecting normal cells by inducing G1/S restriction-point blockade and then using chemotherapy have been tested. For example, staurosporine is capable of inducing G1/S restriction-point blockade in normal cells. This does not occur in neoplastic cells. A clear demonstration that this is also achievable in vitro and leads to selective doxorubicin cytotoxicity has been reported.

In summary, the convergence of learning about mechanisms of drug action together with increasing knowledge about cellular targets and the cell cycle has greatly stimulated the development of cytoprotection as a therapeutic strategy. The cytoprotective agents that are already in the clinic are tangible proof of the validity of this approach. An advantage of this strategy is that once a drug has an established therapeutic efficacy, this becomes a point of departure for enhancing its results. Over the next decade, the advantages of such powerful concepts may overcome the handicaps to their clinical development resulting from the complexity of the studies required to demonstrate an unequivocal therapeutic benefit over the benefit offered by the anticancer drug itself. Nevertheless, this strategy is beginning to capture the attention previously given to biochemical modulation, and may be conceived of in terms of a "yin-yang" relationship with the latter.

Reprinted with permission from Helix, Amgen's magazine of biotechnology (Volume VII, Issue 3, 1998, 48-56).




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  		Photomicrograph of methotrexate (above), an alkylating agent that injures platelets (below) during chemotherapy.

 


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  		Leucovorin, a platelet chemoprotectant.

 



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  		Doxorubicin (above), a well-known chemotherapeutic which damages cardiac muscle (below).

 


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  		Dexrazoxane, the corresponding cytoprotectant.

 





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  		Cisplatin (top) which is known to cause peripheral neuropathy. Synaptic junctions (second from top). (bottom two) Two views of the cytoprotectant, pyridoxine

 


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  		Photomicrograph of glutathione, a cytoprotectant.

 



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  		Carboplatin (top), a member of the platinum family. Platinums are often toxic to the kidney and bladder (below).

 



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  		Glutathione, the corresponding cytoprotectant.

 



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  		Oxonic acid, ammonia (above). Oxonic acid, aqua dest (below). NaOH.

 



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  		Oxonic acid, ammonia, NaOH (above). Oxonic acid, ammonia (below).

 


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   Footnotes
 
Editor's Note: In the original publication of "Shelter from the Storm" (Helix, Vol. VI, 3, 48-56), the graphic and caption describing the gastrointestinal tract wrongly listed leucovorin as the corresponding cytoprotectant for 5-fluorouracil. Leucovorin increases the toxicity of 5-fluorouracil in the gastrointestinal tract. The actual corresponding chemoprotectant is oxonic acid, and is shown correctly here.

Editor's note: The authors have provided these full references for this reprinting of Cytoprotection: Shelter from the Storm. References were not cited, however, within the article as reprinted from Helix.


   References
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  1. Goldin A, Venditti JM, Kline I et al. Eradication of leukemia cells (L1210) by MTX and MTX plus citrovorum factor. Nature 1966;212:1548-1550.
  2. Djerassi I, Agir E, Roger GL Jr. et al. Long-term remissions in childhood acute leukemia: use of infrequent infusions of MTX; supportive roles of platelet transfusions and citrovorum factors. Clin Pediatr 1966;5:502-509.[Abstract/Free Full Text]
  3. Hryniuk WM, Bertino JR. Treatment of leukemia with large doses of methotrexate and folinic acid: clinical-biochemical correlates. J Clin Invest 1969;48:2140-2155.
  4. Jaffe N, Paed D. Recent advances in the chemotherapy of metastatic osteogenic sarcoma. Cancer 1972;30:1627-1631.[Medline]
  5. Jaffe N, Frei E III, Traggis D et al. Adjuvant methotrexate and citrovorum-factor treatment of osteogenic sarcoma. N Engl J Med 1974;291:944-997.
  6. Von Hoff DD, Rozencweig M, Louie AC et al. "Single" agent activity of high-dose methotrexate with citrovorum factor rescue. Cancer Treat Rep 1978;62:233-235.[Medline]
  7. Dorr RT. Chemoprotectants for cancer chemotherapy. Semin Oncol 1991;18(suppl 2):48-58.[Medline]
  8. Dorr RT, Alberts DS, Chen HSG. The limited role of corticosteroids in ameliorating experimental doxorubicin skin toxicity in the mouse. Cancer Chemother Pharmacol 1988;5:17-20.
  9. Dorr RT, Alberts DS. Pharmacologic antidotes to experimental doxorubicin skin toxicity: a suggested role for beta-adrenergic compounds. Cancer Treat Rep 1981;65:1001-1006.[Medline]
  10. Dorr RT, Alberts DS. Modulation of experimental doxorubicin skin toxicity by beta-adrenergic compounds. Cancer Res 1981;416:2428-2432.
  11. Dorr RT, Alberts DS. Failure of DMSO and vitamin E to prevent doxorubicin skin ulceration in the mouse. Cancer Treat Rep 1983;675:499-501.
  12. Monstrey S, Mullick P, Narayanana K et al. Hyperbaric oxygen therapy and free radical production: an experimental study in doxorubicin (adriamycin) extravasation injuries. Ann Plast Surg 1997;38:163-168.[Medline]
  13. Dorr RT, Alberts DS, Stone A. Cold protection and heat enhancement of doxorubicin skin toxicity in the mouse. Cancer Treat Rep 1985;69:431-437.[Medline]
  14. Madhavan S, Northfelt D. Lack of vesicant injury following extravasation of liposomal doxorubicin. J Natl Cancer Inst 1995;87:1556-1557.[Free Full Text]
  15. Patt HM, Tyree EB, Straube RL et al. Technical papers. Cysteine protection against X irradiation. Science 1949;110:213-214.[Free Full Text]
  16. Capizzi R. Amifostine: the preclinical basis for broad-spectrum selective cytoprotection of normal tissues from cytotoxic therapies. Semin Oncol 1996;23(suppl 8):2-17.[Medline]
  17. Yuhas JM, Storer JB. Differential chemoprotection of normal and malignant tissues. J Natl Cancer Inst 1969;42:331-335.
  18. Glover D, Glick JH, Weiler C et al. Phase I trials of WR-2721 and cis-platinum. Int J Radiat Oncol Biol Phys 1984;10:1781-1784.[Medline]
  19. Glick J, Glover D, Weiler R et al. Phase I controlled trials of WR-2721 and cyclophosphamide. Int J Radiat Oncol Biol Phys 1984;10:1777-1780.[Medline]
  20. Kligerman M, Glover D, Turrisi A et al. Toxicity of WR-2721 administered in single and multiple doses. Int J Radiat Oncol Biol Phys 1984;10:1773-1776.[Medline]
  21. Stoller RG, Hande KR, Jacobs SA et al. Use of plasma pharmacokinetics to prevent methotrexate toxicity. New Engl J Med 1977;297:630-634.[Abstract]
  22. Chabner BA, Young RC. Threshold methotrexate concentration for an in-vivo inhibition of DNA synthesis in normal and tumorous target tissues. J Clin Invest 1973;52:1804-1811.
  23. Selby PJ, Lopes N, Mundy J et al. Cyclophosphamide priming reduces intestinal damage in man following high dose melphalan chemotherapy. Br J Cancer 1987;55:531-533.[Medline]
  24. Gore ME, Hills CA, Siddik ZH et al. Priming reduces the bone marrow toxicity of carboplatin. Eur J Cancer Clin Oncol 1987;23:75-80.[Medline]
  25. Howell SB, Markman M. Intraperitoneal chemotherapy: principles and results of clinical trials. In: Muggia FM, ed. Concepts, Clinical Developments, and Therapeutic Advances in Cancer Chemotherapy. Norwell, MA: Martinus Nijhoff Publishers 1987;39-63.
  26. Gupta E, Safa AR, Wang X et al. Pharmacokinetic modulation of irinotecan and metabolites by cyclosporin A. Cancer Res 1996;56:1309-1314.[Abstract/Free Full Text]
  27. Hamers FP, Brakkee JH, Cavalletti E et al. Reduced glutathione protects against cisplatin-induced neurotoxicity in rats. Cancer Res 1993;53:544-549.[Abstract/Free Full Text]
  28. Dorr RT, Von Hoff DD. Cancer Chemotherapy Handbook. 2nd edition. Norwalk, CT: Appleton & Lange 1994;685-688.
  29. Hausheer F, Kanter P, Rustum Y et al. BNP7787 - administration in vivo results in increased therapeutic index and toxicity reduction of platinum drugs. Proc Am Assoc Cancer Res 1998;39:1077a.
  30. Boven E, Hulscher S, Schluper H et al. BNP7787, a new protector against platinum-toxicities, does not influence the anti-tumor efficacy of cisplatin or carboplatin. Proc Am Assoc Cancer Res 1998;39:1078a.
  31. Blum RH. Clinical status and optimal use of the cardioprotectant dexrazoxane. Oncology 1997;11:1669-1677.[Medline]
  32. Chabner B, Longo D. Cancer Chemotherapy and Biotherapy. Hagerstown, MD: Lippincott-Raven, 1996: 2nd Edition; 178-179.
  33. Stolfi RL, Sawyer RC, Martin DS. Failure of L-histidinol to improve the therapeutic efficiency of 5-flourouracil against murine breast tumors. Cancer Res 1987;47:16-20.[Abstract/Free Full Text]
  34. Badary O, Mahmoud N, Al-Sawaf H et al. Effect of L-histidinol on cisplatin nephrotoxicity in the rat. Nephron 1997;77:435-439.[Medline]
  35. Brandes LJ, LaBella FS, Glavin GB et al. Histamine as an intracellular messenger. Biochem Pharmacol 1990;40:1677-1681.[Medline]
  36. Brandes LJ, LaBella FS. Histamine and calcium are independently regulated intracellular mediators of lymphocyte mitogenesis. Biochem Biophys Res Commun 1992;182:786-793.[Medline]
  37. Brandes LJ, Bogdanovic RP, Cawker MD et al. Histamine and growth; interaction of antiestrogen binding site ligands with a novel histamine site that may be associated with calcium channels. Cancer Res 1987;47:4025-4031.[Abstract/Free Full Text]
  38. Brandes LJ, Macdonald LM, Bogdanovic RP. Evidence that the antiestrogen binding site is a histamine or histamine-like receptor. Biochem Biophys Res Commun 1985;126:905-910.[Medline]
  39. Glavin GB, Brandes LJ. Antiulcerogenic and antisecretory effects of a novel diphenylmethamine derivative and antiestrogen binding site ligand. Can J Physiol Pharmacol 1988;66:1139-1143.[Medline]
  40. Glavin GB, Brandes LJ. A novel non-H1, non-H2 histamine antagonist protects against cysteamine-induced duodenal ulcers in rats. Pharmacology 1988;37:277-280.[Medline]
  41. Brandes LJ, LaBella FS, Warrington RC. Increased therapeutic index of antineoplastic drugs in combination with intracellular histamine antagonists. J Natl Cancer Inst 1991;83:1329-1336.[Abstract/Free Full Text]
  42. Brandes LJ, Bogdanovic RP, Cawker MD et al. Histamine and growth; interaction of antiestrogen binding site ligands with a novel histamine site that may be associated with calcium channels. Cancer Res 1987;47:4025-4031.
  43. Brandes L. Proposal for a human clinical trial in small cell lung cancer of DPPE, a novel intracellular histamine antagonist which increases the therapeutic index of various cancer chemotherapy drugs. Canadian Investigational New Drug Application, HPB Control No. 7HP90412602, HPB File No. 9427-U0198-45C, 1991.
  44. Brandes L. University of Manitoba. Patent, International Publication Number WO 94/1861, 1994.
  45. Brandes L, Beecroft W, Hogg G. Stimulation of in vivo tumor growth and phorbol ester-induced inflammation by N,N-diethyl-2-(4-(phenylmethyl)phenoxy) ethanamine HCl, a potent ligand for intracellular histamine receptors. Biochem Biophys Res Commun 1991;179:1297-1304.[Medline]
  46. Brandes L. Proposal for a human clinical trial in small cell lung cancer of DPPE, a novel intracellular histamine antagonist which increases the therapeutic index of various cancer chemotherapy drugs. Canadian Investigational New Drug Application, HPB Control No. 7HP90412602, HPB File No. 9427-U0198-45C, 1991.
  47. Kudoh K, Kikuchi Y, Hiramarsu H et al. Enhancement of antitumor activity of cisplatin by N,N-diethyl-2-(4-(phenylmethyl)phenoxy)ethanamine-HCl in human ovarian cancer cells with intrinsic or acquired resistance to cisplatin. Eur J Cancer 1997;33:122-128, and BMS experiments numbers 391 and 433.
  48. Brandes LJ, LaBella FS, Warrington RC. Increased therapeutic index of antineoplastic drugs in combination with intracellular histamine antagonists. J Natl Cancer Inst 1991;83:1329-1336.
  49. Brandes L. University of Manitoba. Patent, International Publication Number WO 92/11035, 1992.
  50. Brandes LJ, Simons KJ, Bracken SP et al. Results of a clinical trial in humans with refractory cancer of the intracellular histamine antagonist, N,N-diethyl-2-4(4-phenylmethyl)phenoxy)ethanamine-HCl, in combination with various single antineoplastic agents. J Clin Oncol 1994;12:1281-1290.[Abstract/Free Full Text]
  51. Brandes LJ, McDonald KA, Bracken SP et al. Results of a human pilot study testing the hypothesis that the inhibitor histamine antagonist DPPE increases the therapeutic index of doxorubicin. Adv Biosci 1993;89:375-401.
  52. Brandes LJ, Bracken SP, Ramsey EW. N,N-diethyl-2-(4-phenylmethyl)phenoxy) ethanamine in combination with cyclophosphamide: an active, low-toxicity regimen for metastatic hormonally unresponsive prostate cancer. J Clin Oncol 1995;12:1398-1403.
  53. Brandes LJ, Simons KJ, Bracken SP et al. Results of a clinical trial in humans with refractory cancer of the intracellular histamine antagonist, N,N-diethyl-2-4(4-phenylmethyl)phenoxy)ethanamine-HCl, in combination with various single antineoplastic agents. J Clin Oncol 1994;12:1281-1290.
  54. Houghton JA, Houghton PJ, Wooten RS. Mechanism of induction of gastrointestinal toxicity in the mouse by 5-fluorouracil, 5-fluorouridine and 5-fluoro-2'deoxyuridine. Cancer Res 1979;39:2406-2413.[Medline]
  55. Shirasaka T, Shimamota Y, Fukushima M. Inhibition by oxonic acid of gastrointestinal toxicity of 5-fluorouracil without loss of its anti-tumor activity in rats. J Cancer Res 1993;53:4004-4009.
  56. Sorrentino BP, Brandt SJ, Bodine D et al. Selection of drug-resistant bone marrow cells in vivo after retroviral transfer of human MDR1. Science 1992;254:713.
  57. Hanania EG, Fu S, Roninson I et al. Resistance to taxol chemotherapy produced in mouse marrow cells by safety-modified retroviruses containing a human MDR1 transcription unit. Gene Ther 1995;2:279-284.[Medline]
  58. Capizzi RL, Scheffler BJ, Schein PS. Amifostine-mediated protection of normal bone marrow from cytotoxic chemotherapy. Cancer 1993;72(suppl):3495-3501.[Medline]
  59. Patchen ML, MacVittie TJ, Souza LM. Postirradiation treatment with granulocyte-colony-stimulating factor and preirradiation WR-2721 administration synergize to enhance hemopoietic reconstitution and increase survival. Int J Radiat Oncol Biol Phys 1992;22:773-779.[Medline]
  60. Schuchter LM, Meropol N, Glick JH. Radiation and chemotherapy protectors. In: DeVita V, Hellman S, Rosenberg S, eds. Cancer. Principles and Practice of Oncology, 5th edition. Hagerstown, MD: Lippincott-Raven, 1997:3090.
  61. Gabrilove JL, Jakubowski A, Scher H. Effect of granulocytes colony-stimulating on neutropenia and associated morbidity due to chemotherapy for transitional-cell carcinoma of the urothelium. N Engl J Med 1988;318:1414-1422.[Abstract]
  62. Grem JL, McAtee N, Murphy RF et al. Phase I and pharmacokinetic study of recombinant human granulocyte-macrophage colony-stimulating factor given in combination with flourouracil plus calcium leucovorin in metastatic gastrointestinal adenocarcinoma. J Clin Oncol 1994;12:560-568.[Abstract]
  63. Chi K-H, Chen C-H, Chan W-K et al. Effect of granulocyte-macrophage colony stimulating factor on oral mucositis in head and neck cancer patients after cisplatin, flourouracil, and leucovorin chemotherapy. J Clin Oncol 1995;13:2620-2628.[Abstract]
  64. Muggia FM, Green MD, Speyer JL, eds. Cancer Treatment and the Heart. Baltimore: Johns Hopkins University Press, 1992.
  65. Blum RH, Carter SK. Adriamycin: a new drug with significant clinical activity. Ann Intern Med 1974;80:249-259.
  66. Von Hoff DD, Rozencweig M, Layard M et al. Daunomycin-induced cardiotoxicity in children and adults. Am J Med 1977;62:200-208.[Medline]
  67. Speyer JL, Green MD, Kramer E et al. Protective effect of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer. N Engl J Med 1988;319:745-752.[Abstract]
  68. Swain SM, Whaley FS, Gerber MC et al. Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy. J Clin Oncol 1997;15:1318-1340.[Abstract/Free Full Text]
  69. Yuhas JM, Spellman JM, Jordan SW. Treatment of tumors with the combination of WR-2721 and cis-dichlorodiammineplatinum (II) or cyclophosphamide. Br J Cancer 1980;42:574-585.[Medline]
  70. Yuhas JM, Culo F. Selective inhibition of the nephrotoxicity of cis-dichlorodiammine platinum (II) by WR-2721 without altering its anti-tumor properties. Cancer Treat Rep 1980;64:57-64.[Medline]
  71. Glover DJ, Glick JH, Weiler C et al. Phase I/II trials of WR-2721 and cis-platinum. Int J Radiat Oncol Biol Phys 1986;12:1509-1512.[Medline]
  72. Kemp G, Rose P, Lurain J et al. Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer. J Clin Oncol 1996;14:2101-2012.[Abstract/Free Full Text]
  73. Takahashi I, Nagai T, Miyaishi K et al. Clinical study of the radioprotective effects of amifostine on chronic radiation injury. Int J Radiat Oncol Biol Phys 1986;12:935-938.[Medline]
  74. McDonald S, Meyerowitz C, Smudzin T et al. Preliminary results of a pilot study using WR-2721 before fractionated irradiation of the head and neck to reduce salivary gland dysfunction. Int J Radiat Oncol Biol Phys 1994;29:747-754.[Medline]
  75. Tannehill S, Mehta M. Amifostine and radiation therapy past, present, and future. Semin Oncol 1996;23(suppl 8):69-77.[Medline]
  76. Van Groeningen CJ, Leyva A, Kraal I et al. Clinical and pharmacokinetic studies of prolonged administration of high-dose uridine intended for rescue from 5-FU toxicity. Cancer Treat Rep 1986;70:745-750.[Medline]
  77. Holm B, Jensen PB, Sehested M. ICRF-187 rescue in etoposide treatment in vivo. A model targeting high-dose topoisomerase II poisons to CNS tumors. Cancer Chemother Pharmacol 1996;38:203-209.[Medline]
  78. Raghavan D. New approaches in the treatment of bladder cancer. Cancer Invest 1997;15(suppl 1):75-78.
  79. Lund B, Hansen OP, Theilade K et al. Phase II study of gemcitabine (2,2'-difluorodeoxycytidine) in previously treated ovarian cancer patients. J Natl Cancer Inst 1994;86:1530-1534.[Abstract/Free Full Text]
  80. Crino L, Scagliotti G, Marangolo M et al. Cisplatin-gemcitabine combination in advanced non-small cell lung cancer: a phase II study. J Clin Oncol 1997;15:297-303.[Abstract/Free Full Text]
  81. Glover DJ, Glick JH, Weiler C. WR-2721 protects against the hematologic toxicity of cyclophosphamide: a controlled phase II trial. J Clin Oncol 1986;4:584-588.[Abstract/Free Full Text]
  82. Delaflor-Weiss E, Blommaert F, Gill I et al. Amifostine (WR-2721) protects from bone marrow toxicity of combinations of cisplatin (P) and carboplatin (C) without decreasing platinum-DNA adduct formation. 8th NCI/EORTC Symposium on New Drugs and Cancer Therapy. 1994;214a.
  83. Chen X, Herliczek TW, Keyomarsi K. Use of cell cycle checkpoint alterations to maximize therapeutic effectiveness in breast cancer. Proc Am Assoc Cancer Res 1998;39:4436a.




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