In vivo and in vitro study on potential combination therapy of COL 3 and tamoxifen in breast cancer a pilot study

Chapter Introduction 1.1 BACKGROUND 1.1.1 Overview of Current Breast Cancer Therapy The current treatment of breast cancer is a multidisciplinary effort, with goals dependent on the specific clinical situation Various clinical breast cancer treatment are listed in Table 1.1 [1-4] For patients who have not actually developed breast cancer but at high risk for the development of the disease, prevention of the breast cancer with a selective estrogen receptor modulator (tamoxifen) is more frequently used to treat established disease[5, 6] Patients with non-invasive disease (intraductal carcinoma or ductal carcinoma in situ) are now routinely treated with surgery (mastectomy in some cases, breast conservation with or without radiation therapy in others) followed by a treatment with tamoxifen[7-9] Patients with invasive breast cancer are generally treated with surgery followed by adjuvant systemic therapy tailored to their level of risk At the same time, it is common to see patients treat with preoperative (‘neo-adjuvant’) therapy For them, interpretation of operative findings can be a challenge[10-12] Patients with hormone receptor-positive early-stage tumors -almost without regard to tumor size or other risk factors—are routinely offered adjuvant hormonal treatment Tamoxifen remains a gold standard for patients of all ages, but there is increasing evidence regarding the role that aromatase inhibitors may play in postmenopausal patients[13] At present, we know that an average planned course of years of tamoxifen is probably appropriate for most patients Longer or shorter durations might be optimal for selected patients, there is even more reason to carefully evaluate the risks and benefits of ovarian ablation as a component of systemic treatment[14-16] It is apparent that treatment of breast cancer is evolving rapidly and has changed dramatically over the past decade Given the understanding of the basic biology of breast cancer, the pending revolution in our ability to finely subtype it, and the availability of hundreds of novel agents, it seems reasonable to expect the improvements of the past decades to accelerate in the future[17] Table 1.1 Summary of breast cancer treatment Therapy Agent used Surgery purpose remove as much of tumor as possible[1] Doxorubicin Cyclophosphamide Chemotherapy methotrexate use of anti-cancer drugs that go throughout the entire body Fluorouracil to prevent recurrence[2-4] Carmustine (BCNU) 6-mercaptopuri Vincristin Radiotherapy reduce the risk of local recurrence; kill tumor cells that may be living in lymph nodes[2-4] Hormonal therapy Tamoxifen reduce the risk of recurrence Aromatas inhibitors (Letrozole) if tumor expresses estrogen receptors[2-4] Biologic therapy Herceptin (or Trastuzumab) block receptor HER-2/neu[3] 1.1.2 The Role of Angiogenesis in Breast Cancer Angiogenesis, the process of new blood vessel formation, plays a crucial role in local tumor growth and distant metastasis in breast cancer[18] Angiogenesis precedes transformation of mammary hyperplasia to malignancy Transfection of tumor cells with angiogenic stimulatory peptides increases tumor growth, invasiveness, and metastasis Conversely, inhibitors of angiogenesis will decrease growth and metastasis of tumor cells[19] Tamoxifen, initially believed to be a competitive inhibitor of estradiol, may have estrogen-independent mechanisms of action[20] It has been reported that tamoxifen has antiangiogenic activity (Table 1.2) Other agents used in breast cancer, which have antiangiogenic activity, include several chemotherapeutic agents (paclitaxel[21], cyclophosphamide[22], methotrexate[23], etc.), protease inhibitors[24], growth factor/receptor antagonists[25] and endothelial toxins[26] Table 1.2 Antiangiogenic activity of tamoxifen Reference Antiangiogenic activity of tamoxifen Inhibits VEGF (vascular endothelial growth factor) and fibroblast [27, 28] growth factor (FGF)-simulated embryonic angiogenesis Decrease endothelial density and increases the extent of necrosis [29] in MCF-7 tumors growing in nude mice Inhibition of angiogenesis was detected before measurable effects [30] on tumor volume Down-regulation of CD36, a glycoprotein recptor for matrix [31] proteins, thrombospondin-1, and collagen types I and IV 1.1.3 Overview of Combination Therapy in Cancer Treatment Sometimes, more than one type of treatment is used to treat breast cancer Combination therapy may be adjuvant therapy - two types of treatment such as surgery followed by radiation or concurrent therapy - two types of treatment given during the same period of time With surgery becoming more conservative in the amount of tissue that is removed, it is common for even those with early stage cancers to receive combination therapy Examples for combination therapy in breast cancer treatment are shown in Table 1.3 Early in the 1950’s, some encouraging results already showed that combined drug therapy improved the treatment of cancer, even though most patients treated had advanced solid tumors[32, 33] In the past few decades, concept of “synergism” has been developed, that in the combination therapy, chemotherapeutic agents interfere with either differing metabolic pathways or act at different sites in the same pathway This concept of synergism suggested that drugs might be used together to block the formation of essential cellular components, resulting in tumor cell death[34] Several mechanistic concepts evolved, including sequential blockade, or the inhibition of two or more enzyme-mediated steps in the production of a necessary metabolite; concurrent blockade, or the inhibition of two or more parallel pathways in the synthesis of the necessary metabolite; and complementary inhibition, or the interference with different but related biochemical processes[35-37] Table 1.3 Combination Regimens in breast cancer treatment [38] Abbreviation ACe Regimen Doxorubicin 45 mg/m IV day1 Frequency Every to weeks Cyclophosphamide 200 mg/m /d PO days 3-6 CAF Cyclophosphamide 100 mg/m2 /d PO days 1-14 Doxorubicin 30 mg/m2/d IV day1,8 Fluorouracil 500 mg/m /d IV days 1,8 Every weeks until 450mg/m2 of doxorubicin then start methotrexate 40 mg/m2 IV and increase 5-FU to 600mg/m2 IV CMF Cyclophosphamide 100 mg/m2 /d PO days 1-14 Every weeks Methotrexate 40-60 mg/m /d IV days 1,8 Fluorouracil 600 mg/m2/d IV days 1,8 CMFP Cyclophosphamide 100 mg/m2 /d PO days 1-14 Every weeks Methotrexate 60 mg/m /d IV days 1,8 Fluorouracil 700 mg/m2/d IV days 1,8 Prednisone 400 mg/m2/d PO days 1-14 CMFVP Cyclophosphamide 2.5mg/kg PO daily Methotrexate 25-50 mg IV weekly Every week for weeks followed by reduced therapy for maintenance Fluorouracil 12 mg/kg/d IV days 1-4, then 500mg IV weekly Vincristine 0.035 mg/kg IV weekly (max dose mg) Prednisone 0.75 mg/kg PO daily FAC Fluorouracil 500 mg/m2/d IV days 1,8 Every weeks Doxorubicin 50 mg/m /d IV day1 Cyclophosphamide 500 mg/m2 IV days MV1b Mitomycin 15-20 mg/m2 IV day Every 6-8 weeks Vinblastine mg/m IV/d days 1,21 1.2 TAMOXIFEN Ph Z Me N Et Ph O Figure 1.1 Chemical structure of tamoxifen 1.2.1 Chemistry Chemically, tamoxifen is the trans-isomer of a triphenylethylene derivative (Figure 1.1) The chemical name is (Z)2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N- dimethylethanamine 2-hydroxy-1,2,3- propanetricarboxylate (1:1) Tamoxifen citrate has a molecular weight of 563.62, the pKa' is 8.85, the equilibrium solubility in water at 37°C is 0.5 mg/ml and in 0.02 N HCl at 37°C, it is 0.2 mg/ml 1.2.2 Pharmacology Tamoxifen is one of the Selective estrogen receptor modulators (SERMs), which are a class of compounds with interesting pharmacology[39] They have the capability of acting as estrogen receptor (ER) agonists in some tissues and as antagonists in others[40-43] Tamoxifen is a potent ER antagonist, and its major antitumour activity is achieved by competitively inhibiting estradiol binding at the estrogen receptor[40, 44] Therefore, patients with ER positive cancers respond best to tamoxifen treatment [45] 1.2.3 Clinical Use Tamoxifen (Nolvadex) has been the standard hormonal agent used for breast cancer It is the prototype for a growing class of compounds called selective estrogen receptor- modulators (SERMs) SERMs chemically resemble estrogen and trick the breast cancer cells into accepting it in place of estrogen Unlike estrogen, however, they not stimulate breast cancer cell growth Other SERMs being studied for breast cancer include toremifene (which is very similar to tamoxifen), idoxifene, and droloxifene[39] The antiestrogenic effects of tamoxifen are manifest over a wide range of dose A dose of 10 to 20 mg, twice daily, was used in early clinical trials The dose-response effect of tamoxifen was tested over a range of to 100 mg/m2 body surface area, twice daily No clear increase in antitumor activity of tamoxifen was shown with the larger doses[46] Tolerance to tamoxifen is good The most frequent side effect has been hot flushes, which are tolerable in most patients Approximately 10% patients have mild nausea and vomiting that can be quite severe and require interrupting treatment A less frequent side effect is bone pain[47] Other rare side effects include vaginal bleeding, thrombophlebitis, and ocular toxicity[48-50] Tamoxifen can be used in the treatment of metastatic breast cancer in postmenopausal women (Table 1.4) as well as in premenopausal women (adjuvant trials) (Table 1.5) Tamoxifen as adjuvant treatment in postmenopausal has been established as useful, either alone or combined with chemotherapy Table1.4 Tamoxifen in Premenopausal Patients (Phase II studies) Reference Tamoxifen Dose Patients (n) Remarks [51] 20 mg twice daily 10 First trial to show antitumor activity [52] 20 mg twice daily 11 Response observed despite incomplete suppression of ovarian function [53],[54] 20 mg twice daily 74 Median duration of response, 13 months [55] 10 mg twice daily 21 Response duration, to 18 months [56] 10 to 20 mg twice daily 26 No evidence of dose-response relationship [57] 10 mg twice daily 38 Median duration of response, months [58] 10 mg twice daily 44 Response duration, months [59] 20 mg twice daily 43 Median response duration, 20 months Table 1.5 Adjuvant Trials with Tamoxifen in Postmenopausal Patients Reference Patients [60] 588 Dose of Tamoxifen Remarks 20 mg/day Trend toward increase in survival but not significant [61] 656 40 mg/day No difference in survival [62] 1135 10 mg twice daily Significant increase in survival of patients treated with tamoxifen [63] 503 20 mg/day Survial similar; estrogen receptors unknown in 52% of patients [64] 1650 10 mg twice daily Trend toward improved survival with tamoxifen; estrogen receptors unknown in 80% patients [65] 170 10 mg twice daily Survial unchanged; estrogen receptors [66] 400 10 mg twice daily Survival unchanged except for a trend positive in 85 % in progesterone-receptor-positive tumors [67] 1312 20 mg/day Significant increase in survival of all patients [68] 179 40 mg/day Significant improvement in 5-year survival of patients with receptorpositive tumors 1.2.4 Pharmacokinetics 1.2.4.1 Human Study Absorption Tamoxifen is rapidly absorbed from the gastrointestinal tract[69] Its bioavailability is high (approximately 100%) and independent of dose, suggesting minimal first-pass metabolism[70, 71] Following single-dose administration of tamoxifen 40 mg, peak plasma concentration (Cmax) was approximately 65 μg/L and time to Cmax (tmax) was reached in 3-4 hours in healthy subjects[72] Cmax was dose dependent[73] Distribution Tamoxifen is highly lipophilic agents, resulting in extensive plasma protein binding (>95%), with the majority bound to albumin[44, 71, 74] Complete tissue distribution studies have been conducted in animals using [14C]tamoxifen High concentrations of radioactivity were found in the breast tissue, uterus, liver, kidney, lung and pancreas[75] A human study of tamoxifen distribution was conducted by Lien et al[76] in 14 patients ranged in age from 28 to 89 years of age, and biopsies were recovered during surgery or autopsy over the course of years High concentrations of tamoxifen were found in liver, lung, pancreas, brain, ovaries and breast tissue Distribution of tamoxifen in the human uterus was studied by Fromason and Sharp[77] in women prior to hysterectomy Tamoxifen has a high affinity for the endometrium, as tamoxifen concentrations were found to be 2-3 times higher in the uterus than in plasma[77, 78] In humans, the apparent volume of distribution was approximately 50-60 L/kg[79] Metabolism Tamoxifen undergoes phase I metabolism in the liver by microsomal cytochrome P450 (CYP) enzymes[80, 81] Tamoxifen is mostly metabolized by CYP3A and CYP2C isoforms[82], but CYP2D6 may also be involved The major metabolites of tamoxifen are N-desmethyltamoxifen (resulting from N-demethylation) and 4-hydroxytamoxifen (resulting from 4-hydroxylation)[83-85] Excretion Tamoxifen is excreted in the bile and eliminated through the faces, with small amounts eliminated in the urine[44, 78, 83] Following oral administration of tamoxifen, elimination is biphasic and is dependent on the cumulative dose The terminal elimination half-life (t1/2β) of tamoxifen is 5-7 days, which may be due to enterohepatic circulation, plasma protein binding and autoinhibition of metabolism[44, 71, 81, 83, 86, 87] Steady-state pharmacokinetics Steady-state serum concentrations of tamoxifen are usually achieved within 3-4 weeks of daily tamoxifen administration at dosage ranging between 20 and 40 mg/day[44, 74, 83] The average steady-state concentrations for dosage of 20mg/day (long-term treatment) and 40 mg/day (2month treatment) ranged from 164-494 and 186-214 μg/L, respectively[74, 88, 89] The area under the concentration-time curve (AUC) for tamoxifen following a regimen of 10 mg tamoxifen twice daily for 21 days was 1597μg·h/L in women with advanced breast cancer[90] 10 54 Pritchard, K.I., et al., Tamoxifen 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