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Systemic Lipoplatin Infusion Results in Preferential Tumor Uptake in Human Studies

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Systemic Lipoplatin Infusion Results in Preferential Tumor Uptake in Human Studies ANTICANCER RESEARCH 25: 3031-3040, (2005) _______________________________________________________________________________________________ Systemic Lipoplatin Infusion Results in Preferential Tumor Uptake in Human Studies T ENI BOULI K AS1, GEO RGE P. STAT HOPO U LOS 2, N IKOL A OS VO LAKA K IS1 and MARIA VOUG I OUKA 1 , 1Regulon, Inc. 715 Nor th Shoreline Blvd., Mountain View, C alifornia 94043, U.S.A. and Regulon AE, Grigoriou Afxentiou7, Athehs 174 55; 1Errik os Dunant Hos pital, Mes ogeion 107, Athens 15128, Gr eece ; Abstract. LipoplatinTM, a liposomal formulation of cisplatin, Key words: Lipoplatin, cisplatin, tumor targeting, gastric cancer, colon was developed with almost negligible nephrotoxicity, ototoxic ity , cancer, hepatocellular cancer. and ne urotoxicity as demonstrated in prec linical and Phase I human studies. A polyethy le ne-gly col c oating of the liposome w ith a m odel where Lipoplatin damage s more tumor c ompare d to nanoparticles is s upposed to r e sult in tumor accum ulation of the normal c ells. In c onclusion, Lipoplatin has the ability to drug by extravas ation through the altere d tumor vasculatur e. We prefe r entially conce ntr ate in malignant tis sue both of primar y and e xplored the hypothe s is that intrav e nous infusion of Lipoplatin m etastatic origin following intravenous infusion to patients. In r esults in tumor targeting in four independent patient c ases (one this respect, Lipoplatin emerges as a very promising drug in the w ith hepatocellular adenoc ar cinom a, two w ith gastr ic cancer, arsenal of chemotherapeutics. and one with colon c ancer ) w ho under went Lipoplatin infusion followed by a pr esche dule d s urger y ~ 20h later. D irec t m easurem ent of platinum le vels in s pecim e ns fr om the exc ised Cis-dichlorodiammineplatinum (II) (Cisplatin) continues to play tumor s and normal tissues showe d that total platinum lev els w ere a central role in chemotherapy, for the treatment of epithelial on the aver age 10-50 times higher in m alignant tiss ue c ompare d malignancies, for over 20 years, since its serendipitous to the adjacent normal tissue s pecim ens; most effec tive targeting discovery in 1965 (1) and its identification in 1969 (2,3, w as observ e d in colon c ancer w ith an accumulation up to 200- reviewed in 4,5). The antitumor properties of cisplatin are fold higher in c olon tumors compare d to normal c olon tissue. Of attributed to the kinetics of its chloride ligand displacement the s e veral s urgic al specime ns , gastric tumor s displaye d the reactions leading to DNA crosslinking activities; indeed, once highes t lev els of total platinum suggesting Lipoplatin as a inside the cell, the lower chloride ion content of the cytoplasm c andidate anticanc er agent for gastric tumors; gastric tumor allows the two chloride groups of cisplatin to exchange with s pecim ens had up to 260 m icrogr am s platinum /g tiss ue that w as water yielding the diaquo (hydroxo) species. Although cisplatin higher than any tissue lev el in animals treate d at much higher reacts directly with sulfur groups (such as glutathione) the doses . Fat tissue display e d a high accum ulation of total platinum reaction of cisplatin with DNA depends on its prior hydrolysis to in surgical spe c imens in three differe nt patients c orre lating to the hydroxo complexes that are much more reactive with nitrogen lipid capsule of c isplatin in its Lipoplatin formulation. It was also and oxygen donor groups on proteins and DNA. The diaquo inferr ed that normal tissue had m ore platinum trapped in the species of cisplatin was found in early studies to react with tissue but not r eacted with macromolec ule s where as tumor tiss ue pyrimidines and substituted pyrimidines and to achieve displaye d platinum that re acte d with cellular macromole c ules; the spectacular cures of ascites Sarcoma 180 tumors in Swiss mice data wer e consis te nt (6). Intensive work toward improvement of cisplatin, and with hundreds of platinum drugs tested resulted in the introduction of carboplatin and of oxaliplatin used only for a very narrow ____________________________________________________ spectrum of cancers. Cisplatin, carboplatin, oxaliplatin and most other platinum Correspondence to: Dr Teni Boulikas, Ph.D., Regulon, A.E., 7 compounds induce similar types of damage to DNA and their Grigoriou Afxentiou, Alimos, Athens 17455, Greece; Tel: +30-210- tumor killing properties largely depend on their ability to induce 9858454; Tel/Fax: +30-210-9858453, e-mail: [email protected] apoptosis; this is mediated by activation of signal transduction leading to the death receptor mechanisms as well as 3031 ANTICANCER RESEARCH 25: 3031-3040, (2005) ___________________________________________________________________________________________________________ mitochondrial pathways. Cisplatin has the talent to elicit patients (25). The mechanism of ototoxicity involves loss of crosslinks in DNA confronting the DNA repair machinery. inner and outer hair cells of the basal turns of the cochlear, loss Furthermore, cisplatin alters signal transduction and apoptotic of spinal ganglion cells and degeneration of the stria vascularis pathways crosstalking to other signaling pathways such as those (26,27) caused by induction of apoptosis in these cell types leading to upregulation of transcription factor and (reviewed in 8). nuclear/cellular enzymes (reviewed in 7-9). The unique anticancer properties of cisplatin have prompted Platinum drugs elicit a distinct pattern of side effects numerous attempts to either improve its therapeutic efficacy or depending on their reaction with blood components, tissue to reduce its side effects without compromising therapeutic biodistribution, half-life in plasma, ability to cross the cell efficacy. Modifications have focused either in formulations of membrane in tissue targets, and molecular mechanisms cisplatin aimed at enhancing its tumor targeting to minimize including, reactivity to various types of macromolecules damage to nonmalignant tissue and to lower the side effects or to especially DNA, type of DNA reaction products, extend of chemical modifications on the molecule to derive molecules of damage to normal compared to malignant tissue, rate of repair of better qualities. DNA damage by particular cell types and a number of other LipoplatinTM, is a novel liposomal formulation of cisplatin parameters. The clinical use of cisplatin is impeded by a cute formulated into liposomes composed of dipalmitoyl toxicities , s uch a s nausea a nd vomiting (GI tract toxicity), and phosphatidyl glycerol (DPPG), soy phosphatidyl choline (SPC- cumulative dose-dependent chronic side effects of 3), cholesterol and methoxy-polyethylene glycol–distearoyl nephrotoxicity, ototoxicity, a nd ne urotoxicity as a result of phosphatidylethanolamine (mMPEG2000-DSPE). In a previous damage of cells in these tissues (reviewed in 7,10). Since the work Lipoplatin was shown to be less toxic than cisplatin in reduction of the renal side effects with hydration and of the animals and to cause reduction of tumors after intraperitoneal or gastrointestinal side effects with antiemetics, neurotoxicity is the intravenous injection to human breast MCF-7 or prostate LNCaP most important adverse effect associated with cisplatin xenografts (28); histological examination of the treated tumors chemotherapy occurring in 47% among 292 ovarian cancer from mouse xenografts was consistent with apoptosis in the patients treated with cisplatin combinations at conventional tumor in a mechanism similar to that of cisplatin. Mice and rats doses in randomized controlled studies compared to 25% of injected with cisplatin developed renal insufficiency with clear patients treated with the non-cisplatin-containing regimens (11). evidence for tubular damage, but those injected with the same The symptoms include numbness, tingling, paresthesiae in the dose of Lipoplatin were free of kidney injury (29). In a Phase I extremeties, difficulty in walking, decreased vibration sense in study involving 27 patients Lipoplatin dose escalation was the toes, deep tendon reflexes, loss of the ankle jerks, difficulty administered as second or third line chemotherapy; Lipoplatin with manual dexterity, difficulty with ambulation from a deficit showed no nephrotoxicity and it lacked the other serious side in proprioception and gait disturbances; less frequent symptoms effects of cisplatin up to a dose of 125 mg/m2 every 14 days; the from cisplatin neurotoxicity include retrobulbar neuritis, MTD was above 350 mg/m2 as a single infusion (30). encephalitic symptoms, autonomic neuropathy, cerebral Because Lipoplatin nanoparticles bear a PEG-coating it can herniation, seizures, cortical blindness, ophthalmologic effects, be inferred that intravenous infusion of this drug shall result in and vertigo (12-15). Unfortunately, neuropathy is long-term with its preferential distribution at tumor sites via extravasation significant worsening of the symptoms in the first 4 months (16) through the leaky tumor vasculature in analogy to PEGylated that may persist for over 52 months after stopping cisplatin DOXIL/Caelyx liposomal doxorubicin (31). The objective of the treatment (17). Higher platinum concentrations in tissues from present study was to investigate the possibility of platinum the peripheral nervous system (peripheral nerves and dorsal root accumulation in solid human tumors after Lipoplatin infusion in ganglia) compared to tissues from the central nervous system cancer patients. Single doses of 100 mg/m 2 Lipoplatin were used (brain, spinal cord) seem to correlate with clinical symptoms of that are known not to cause any adverse reactions (30). peripheral neuropathy (18). Attempts to prevent cisplatin- induced neurotoxicity may involve treatment of patients with Patients and methods nucleophilic sulfur thiols (amifostine, diethyldithiolcarbamate and others), adrenocorticotropic hormone analogs (ORG 2766) Prepar ation and character istic s of Lipoplatin. C ispla tin w as and calcium channel antagonists (19). Never the less, the clinical purchase d from H eraeus /Flavine (mw 300). The lipid s hell of relevance of the protective effect is small (20-22).
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