Chemotherapy is still one of the most widely used anticancer therapies. It is mostly about inhibiting the proliferation of rapidly dividing cells, so it is not selective for tumor cells. As a result, many undesirable side effects are associated with chemotherapy. The disadvantageous properties of chemotherapeutics can be largely eliminated by using conjugates of polymers with low molecular weight drugs. An example of such a conjugate is a doxorubicin-linked HPMA polymer. In addition to the properties obtained by polymer binding, such as achieving solubility in aqueous solutions, reducing systemic toxicity, increasing the maximum tolerated dose, or passive targeting by the EPR effect, the fact that doxorubicin induces immunogenic cell death is used in therapy with this drug. It has already been shown that after complete cure of the experimental mice with polymeric conjugates of HPMA with doxorubicin, some mice develop long-term resistance to re-inoculation with a lethal dose of tumor cells. Resistance is specific to the particular line of tumor cells from which the mouse was cured, and CD8+ cytotoxic T cells and IFNγ play an important role. In this work, we monitored changes in the proportion of immune populations and their activation markers after treatment with HPMA-based polymers with doxorubicin...

Indiana University-Purdue University Indianapolis (IUPUI) / Colorectal cancer is the third most common type of cancer and the third most common cause of cancer-related mortality. There are three types of treatment available to patients, either individually or in combination. Treatments are radiation, chemotherapy, and surgery. In a Phase II clinical trial at IUSM, a multimodality approach was chosen. The patients with locally advanced rectal cancer received preoperative treatment with capecitabine and irinotecan (CPT-11) combination followed by chemoradiation with capecitabine and finally surgery to improve response and decrease local recurrence. Irinotecan and Capecitabine are both prodrugs activated in vivo to SN-38 and 5-FU, respectively. Identification of the molecular markers for 5-FU and Irinotecan efficacy and toxicity is important for the development of more efficient and less toxic treatment strategies for patients with colorectal cancer. The goal of this study was to determine the expression levels of the genes involved in activation and metabolism of capecitabine and irinotecan in pre and post treatment specimens from these patients. The genes quantitated by real-time PCR were carboxylesterase 1 and 2 (CES1 and CES2), thymidylate synthase (TS), β-glucoronidase (β-GUS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD) and topoisomerase I (Topo I). The UGT1A1*28 polymorphism in UDP glucuronosyltransferase 1 is associated with SN-38 toxicity. Therefore, the UGT1A1*28 polymorphism status in patients was determined by PCR-sequencing. Correlative analysis of gene expression and UGT1A1*28 mutation with clinical outcome in this Phase II study was completed.

AQ4N (banoxantrone) is a prodrug that, under hypoxic conditions, is enzymatically converted to a cytotoxic DNA-binding agent, AQ4. Incorporation of AQ4N into conventional chemoradiation protocols therefore targets both oxygenated and hypoxic regions of tumors, and potentially will increase the effectiveness of therapy. This current pharmacodynamic and efficacy study was designed to quantify tumor exposure to AQ4 following treatment with AQ4N, and to relate exposure to outcome of treatment. A single dose of 60 mg/kg AQ4N enhanced the response of RT112 (bladder) and Calu-6 (lung) xenografts to treatment with cisplatin and radiation therapy. AQ4N was also given to separate cohorts of tumor-bearing mice 24 hours before tumor excision for subsequent analysis of metabolite levels. AQ4 was detected by high performance liquid chromatography/mass spectrometry in all treated samples of RT112 and Calu-6 tumors at mean concentrations of 0.23 and 1.07 microg/g, respectively. These concentrations are comparable with those shown to be cytotoxic in vitro. AQ4-related nuclear fluorescence was observed in all treated tumors by confocal microscopy, which correlated with the high performance liquid chromatography/mass spectrometry data. The presence of the hypoxic marker Glut-1 was shown by immunohistochemistry in both Calu-6 tumors and RT112 tumors, and colocalization of AQ4 fluorescence and Glut-1 staining strongly suggested that AQ4N was activated in these putatively hypoxic areas. This is the first demonstration that AQ4N will increase the efficacy of chemoradiotherapy in preclinical models; the intratumoral levels of AQ4 found in this study are comparable with tumor AQ4 levels found in a recent phase I clinical study, which suggests that these levels could be potentially therapeutic.

Siekiant pagreitinti 5-aminolevulino rūgšties (5-ALA) skvarbą į (pro) odą ir sudaryti terapines fotodinaminiam gydymui tinkamas jos koncentracijas, įvertinta 5-ALA ir naujo provaisto skvarba į (pro) odą iš įvairių vietinio poveikio vaisto formų. Atlikta naujo provaisto 2-(dimetilamino)-etil-5-amino-4-oksopentanoato (DMAE-ALA) sintezė, ištirtos jo charakteristikos. Nustatytas susintetinto provaisto stabilumas įvairių pH verčių buferiniuose vandeniniuose tirpaluose ir odos esterazių poveikyje, įrodytas provaisto tinkamumas pernašai į (pro) odą. Atlikti 5-ALA ir du teigiamus krūvius vaisto formoje įgaunančio provaisto jontoforetinės ir pasyvios pernašos iš buferinių tirpalų ir celiuliozinės bei polivinilkarboksilinės kilmės polimerinių gelių į (pro) odą tyrimai in vitro. Patvirtintas reikšmingas skatinamas jontoforezės poveikis krūvinių molekulių pernašai į (pro) odą ir krūvio dydžio reikšmė elektros srovės skatinamos pernašos greičiui. Ištirta vaisto formų, pagamintų iš polivilinkarboksilinės kilmės ir celiuliozės polimerų, kokybė ir jų pasyvioji bei jontoforetinė pernaša. Įrodyta, kad provaisto įterpimui naudojant celiuliozės polimerų pagrindu pagamintus gelius, pasiekiama didžiausia 5-ALA pernaša. Nustatyta, kad du krūvius turintis 5-ALA provaistas į (pro) odą skverbėsi geriau negu vieną krūvį įgaunantys arba elektriškai neutralūs 5-ALA dariniai. Sudarytos rekomendacijos, skirtos pasiekti didžiausiai 5-ALA pernašai į (pro) odą. / Passive and iontophoretic delivery of 5-aminolevulinic acid and newly synthesized prodrug into (through) skin from various topical formulations was evaluated, while trying to accelerate the penetration of 5-ALA and its derivative into (through) skin and to generate the therapeutic concentration suitable for photodynamic therapy. A new prodrug 2-(dimethylamino)-ethyl-5-amino-4-oxopentanoate (DMAE-ALA) was synthesized, its characteristics have been evaluated. Stability of the prodrug in aqueous solutions of various pH values and at exposure with skin esterases (dermal and epidermal stability) has been evaluated. Suitability of the prodrug for topical delivery was confirmed. Studies for the evaluation of 5-ALA and DMAE-ALA passive and active delivery from cutaneous solutions, cellulose and polyvinyl carboxy polymer gels into (through) skin in vitro have been performed. Significant effect of iontophoresis on delivery of charged molecules into (through) skin as well as the significance of the charge of the molecule on the delivery rate has been confirmed. It has been shown that the insertion of the prodrug into cellulose-based polymer gels produces the highest amount of 5-ALA delivered into (through) skin. It was determined that the two-charged prodrug DMAE-ALA penetrated into (through) the skin more efficiently than single-charged or electrically neutral 5-ALA derivatives. Recommendations for achieving most efficient 5-ALA delivery into (through) the skin have been composed.