An innovative approach for cancer therapy implies the use of drugs covalently conjugated to macromolecular carriers that specifically target molecules over-expressed on tumor cells. This drug delivery strategy may allow a controlled release of the drug and a high targeting selectivity on tumor cells, increasing drug cytotoxicity and decreasing its undesirable side effects. We provide in vitro and in vivo preclinical data on the antitumor efficacy of ONCOFID™-S, a new bioconjugate of hyaluronic acid (HA) with SN-38 (the CPT11 active metabolite), that support the validity of the drug delivery strategy implying the use of HA as macromolecular carrier of antineoplastic drugs, an approach based on the over-expression of its target CD44 (the receptor for HA-mediated motility) in a wide variety of cancers. We show that ONCOFID™-S exerts a strong in vitro anti-proliferative activity on CD44 over-expressing rat DHD/K12/trb colon adenocarcinoma cells, as well as on gastric, breast, oesophageal, ovarian and lung human cancer cells, higher than that exerted by unconjugated SN-38. We also demonstrated the in vivo anti-tumor efficacy of locoregional treatment with ONCOFID™-S on two pre-clinical models of colorectal cancer (CRC) in BDIX rats: a) syngeneic model of subcutaneous tumor; b) syngeneic model of metastatic tumor induced by injection of cells into the peritoneal cavity, mimicking the clinical situation of peritoneal carcinomatosis. Specifically, in the latter model ONCOFID™-S is able to dramatically reduce all parameters indicative of a poor prognosis in peritoneal metastatization of CRC without any myelotoxicity or mesothelial inflammation. We propose this CD44-targeted therapeutic strategy for locoregional treatment of peritoneal carcinomatosis from CRC, against which systemic chemotherapy results almost inefficient.

Fifty cases of Hodgkin's disease in intravenous drug users (IVDU) have been collected by the Italian Cooperative Group on AIDS-Related Tumors (G.I.C.A.T.). Ninety-two per cent of the patients were males; the median age was 26 years. Persistent generalized lymphadenopathy (PGL) at onset was present in 54% of patients, AIDS in 9%, ARC in 9% while 28% were simply HIV-positive. The initial median absolute number of CD4 lymphocytes was 264/mmc. Opportunistic infections were diagnosed in 20% of patients. In most patients the histological pattern was that of mixed cellularity and lymphocytic depletion (76%). In almost half the initial symptom was a persistent lymph node enlargement due to PGL. In the majority of patients (58%) only a clinical staging and bone marrow biopsy could be performed due to the presence of opportunistic infections, rapid disease progression or refusal of pathologic staging procedures. One patient presented with a Waldeyer's ring involvement, but no other unusual presentations were observed. After MOPP alternated or followed by ABVD or MOPP alone, 15/29 CR (52%) and 14/29 PR (48%) were observed. The median duration of CR was 14 months, while the median survival of CR has not been reached; the median survival of patients treated with chemotherapy with CD4 values at presentation {geq}400/mmc was significantly superior to that in those with CD4 < 400/mmc. The overall median survival was 16 months. Twenty-eight per cent of patients receiving chemotherapy + radiotherapy developed opportunistic as well as non-opportunistic infections (21%). Lethal hepatic toxicity was observed in 2 patients. In conclusion, Hodgkin's disease in IVDU was not found to be associated with unusual presentations, as previously reported for homosexuals. Complete remissions could be achieved in over 50% of patients, but in IVDU non-opportunistic infections in addition to opportunistic infections may also limit treatment administration. The presence of parenchymal functional impairment due to drug abuse, or drug abuse-related infections, such as pneumonia, endocarditis and hepatitis, should lead to the choice of antitumour agents with no or only minor potential liver, lung and cardiac toxicity.